Factor XIa macrocycle inhibitors bearing a non-aromatic P2&#39; group

ABSTRACT

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. § 371of International Patent Application No. PCT/US2016/044363, filed Jul.28, 2016, which claims priority to U.S. Provisional Application Ser. No.62/198,188, filed Jul. 29, 2015, the entire content of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are inhibitors of factor XIa and/orplasma kallikrein, compositions containing them, and methods of usingthem, for example, for the treatment or prophylaxis of thromboembolicdisorders, or for the treatment of retinal vascular permeabilityassociated with diabetic retinopathy and diabetic macular edema.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thusdiscovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to factor VII(FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates factor IX (FIX) and factor X (FX) that leads to the productionof factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for anti-thrombotic therapy.

Plasma prekallikrein is a zymogen of a trypsin-like serine protease andis present in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Plasma kallikrein is thought to play arole in a number of inflammatory disorders. The major inhibitor ofplasma kallikrein is the serpin C1 esterase inhibitor. Patients whopresent with a genetic deficiency in C1 esterase inhibitor suffer fromhereditary angioedema (HAE) which results in intermittent swelling offace, hands, throat, gastro-intestinal tract and genitals. Blistersformed during acute episodes contain high levels of plasma kallikreinwhich cleaves high molecular weight kininogen liberating bradykininleading to increased vascular permeability. Treatment with a largeprotein plasma kallikrein inhibitor has been shown to effectively treatHAE by preventing the release of bradykinin which causes increasedvascular permeability (A. Lehmann “Ecallantide (DX-88), a plasmakallikrein inhibitor for the treatment of hereditary angioedema and theprevention of blood loss in on-pump cardiothoracic surgery” Expert Opin.Biol. Ther. 8, p 1187-99).

The plasma kallikrein-kinin system is abnormally abundant in patientswith advanced diabetic macular edema. It has been recently publishedthat plasma kallikrein contributes to retinal vascular dysfunctions indiabetic rats (A. Clermont et al. “Plasma kallikrein mediates retinalvascular dysfunction and induces retinal thickening in diabetic rats”Diabetes, 2011, 60, p 1590-98). Furthermore, administration of theplasma kallikrein inhibitor ASP-440 ameliorated both retinal vascularpermeability and retinal blood flow abnormalities in diabetic rats.Therefore, a plasma kallikrein inhibitor should have utility as atreatment to reduce retinal vascular permeability associated withdiabetic retinopathy and diabetic macular edema. Other complications ofdiabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy andneuropathy, all of which have associations with plasma kallikrein mayalso be considered as targets for a plasma kallikrein inhibitor.

To date, no small molecule synthetic plasma kallikrein inhibitor hasbeen approved for medical use. The large protein plasma kallikreininhibitors present risks of anaphylactic reactions, as has been reportedfor Ecallantide. Thus there remains a need for compounds that inhibitplasma kallikrein, that do not induce anaphylaxis and that are orallyavailable. Furthermore, the molecules in the known art feature a highlypolar and ionizable guanidine or amidine functionality. It is well knownthat such functionalities may be limiting to gut permeability andtherefore to oral availability.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectiveinhibitors of serine protease enzymes, especially factor XIa and/orplasma kallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the invention may be used in the treatment of retinalvascular permeability associated with diabetic retinopathy and diabeticmacular edema.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein:L is independently selected from

is an optional bond;

Q is independently selected from O, NH, and CH₂;

Y is independently selected from N and CR⁷;

ring A is independently selected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkylsubstituted with 0-4 R^(e), OR^(b), and C₃₋₅ cycloalkyl substituted with1-4 R⁶;

R³ is independently selected from H, C₁₋₄ alkyl substituted with 1-5 R⁵,C₂₋₄ alkenyl substituted with 1-5 R⁵, C₂₋₄ alkynyl substituted with 1-5R⁵, CN, —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R^(c),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; optionally, two adjacent R³ groups on the carbocyclyl andheterocyclyl may form a ring substituted with 1-5 R⁵;

R^(3a) is independently selected from H and C₁₋₄alkyl;

alternatively, R^(3a) and R³ are taken together to form a heterocyclicring comprising carbon atoms and 1-3 heteroatoms selected from O,NR^(3b), S, wherein the heterocyclic ring is substituted with R^(3c);

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵;

R^(3c) is independently selected from H, NO₂, ═O, halogen, C₁₋₄ alkylsubstituted with 1-5 R⁵, C₂₋₄ alkenyl substituted with 1-5 R⁵, C₂₋₄alkynyl substituted with 1-5 R⁵, CN, —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R^(c),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵;

R⁴ is independently selected from H, halogen, CN, —(CH₂)_(n)NR^(a)R^(a),C₁₋₆ alkyl substituted with 1-5 R¹⁰, —(CH₂)_(n)OR^(b),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R^(c),—(CH₂)_(n)-aryl substituted with 1-5 R¹⁰, —(CH₂)_(n)—C₃₋₆ cycloalkylsubstituted with 1-5 R¹⁰, and —(CH₂)_(n)-4-6 membered heterocyclylsubstituted with 1-5 R¹⁰;

R⁵, at each occurrence, is independently selected from H, D,—(CH₂)_(n)—OR^(b), ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—C₃₋₁₀ carbocyclylsubstituted with 0-5 R^(e), —(CH₂)_(n)-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e), and —O-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e);

R⁶ is independently selected from H, OH, ═O, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OH,—(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle substituted with 0-5 R^(e), —(CH₂)_(n)-4- to 10-memberedheterocycle substituted with 0-5 R^(e), and —(CH₂)_(n)-4- to 10-memberedheterocycle substituted with 0-5 R^(e);

R⁷ is independently selected from H, CN, OR^(b), halogen, NR^(a)R^(a),and C₁₋₃ alkyl substituted with 0-5 R^(e);

R⁸ is independently selected from H, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄alkoxy, CF₃, CN, C₃₋₆ cycloalkyl, aryl, and 5- to 6-memberedheterocycle;

R¹⁰, at each occurrence, is independently selected from H, halogen, CN,NO₂, ═O, C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆ alkyl substituted with 0-5R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substitutedwith 0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl substituted with 0-5 R^(e);

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e);

R^(b), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R_(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e);

R^(c), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl;

R^(d), at each occurrence, is independently selected from H andC₁₋₄alkyl substituted with 0-5 R^(e);

R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heterocyclyl, CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and—(CH₂)_(n)NR^(f)R^(f);

R^(f), at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl, orR^(f) and R^(f) together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In a second aspect, the present disclosure provides a compound ofFormula (I), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of the firstaspect, wherein:

L is independently selected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkyl,OR^(b), and C₃₋₅ cycloalkyl;

R³ is independently selected from H, C₁₋₄ alkyl substituted with 1-5 R⁵,C₂₋₄ alkenyl substituted with 1-5 R⁵, C₂₋₄ alkynyl substituted with 1-5R⁵, CN, —OR^(b), —(CH₂)_(n)—NR^(a)R^(a), —(CH₂)_(n)—C(═O)R^(b),—(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)R^(b), —NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a),—NR^(a)C(═S)NR^(a)C(═O)R^(b), —S(═O)_(p)R^(c), —S(═O)_(p)NR^(a)R^(a),—NR^(a)S(═O)_(p)NR^(a)R^(a), —NR^(a)S(═O)_(p)R^(c), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 1-5 R⁵, and —(CH₂)_(n)-4- to 10-memberedheterocyclyl substituted with 1-5 R⁵; optionally, two adjacent R³ groupson the carbocyclyl and heterocyclyl may form a ring substituted with 1-5R⁵;

R^(3a) is independently selected from H and C₁₋₄alkyl;

alternatively, R^(3a) and R³ are taken together to form a heterocyclicring comprising carbon atoms and 1-3 NR^(3b), wherein the heterocyclicring is substituted with R^(3c);

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵;

R^(3c) is independently selected from H, NO₂, ═O, halogen, and C₁₋₄alkyl substituted with 1-5 R⁵;

R⁴ is independently selected from H, halogen, CN, C₁₋₆ alkyl substitutedwith 1-5 R¹⁰, —OR^(b), —(CH₂)_(n)-aryl substituted with 1-5 R¹⁰,—(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 1-5 R¹⁰, and —(CH₂)_(n)-4-6membered heterocyclyl substituted with 1-5 R¹⁰;

R⁵, at each occurrence, is independently selected from H, D,—(CH₂)_(n)—OR^(b), ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—C₃₋₁₀ carbocyclylsubstituted with 0-5 R^(e), —(CH₂)_(n)-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e), and —O-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e);

R⁷ is independently selected from H, OR^(b), halogen, NR^(a)R^(a), andC₁₋₃ alkyl;

R¹⁰, at each occurrence, is independently selected from H, halogen, CN,NO₂, ═O, C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆ alkyl substituted with 0-5R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substitutedwith 0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl substituted with 0-5 R^(e);

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e);

R^(b), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e);

R^(c), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl;

R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heterocyclyl, CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and—(CH₂)_(n)NR^(f)R^(f);

R^(f), at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl, orR^(f) and R^(f) together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In a third aspect, the present disclosure provides a compound of Formula(II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of the first or second aspect,wherein:

L is independently selected from

ring A is independently selected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkyl, andOH;

R³ is independently selected from —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a);

R^(3a) is independently selected from H and C₁₋₄alkyl;

alternatively, R^(3a) and R³ are taken together to form a heterocyclicring selected from

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵;

R^(3c) is independently selected from H, ═O, and C₁₋₄ alkyl substitutedwith 1-5 R⁵;

R^(4a) is independently selected from H, halogen, CN, OCH₃, OCF₃, CH₃,C(═O)CH₃, CHF₂, CF₃, CCH₃F₂, OCHF₂, aryl, C₃₋₆ cycloalkyl, and 4-6membered heterocycle, wherein said aryl, cycloalkyl and heterocycle isoptionally substituted with R¹⁰;

R^(4b) is independently selected from H and halogen;

R^(4c) is independently selected from H, F, Cl, methyl, ethyl,isopropyl, and OCH₃;

R⁵, at each occurrence, is independently selected from H, D,—(CH₂)_(n)—OR^(b), ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—C₃₋₁₀ carbocyclylsubstituted with 0-5 R^(e), —(CH₂)_(n)-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e), and —O-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e);

R⁷ is independently selected from H and C₁₋₃ alkyl;

R¹⁰, at each occurrence, is independently selected from H, halogen, CN,NO₂, ═O, C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆ alkyl substituted with 0-5R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substitutedwith 0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl substituted with 0-5 R^(e);

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e);

R^(b), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e);

R^(c), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl;

R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heterocyclyl, CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and—(CH₂)_(n)NR^(f)R^(f);

R^(f), at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl, orR^(f) and R^(f) together with the nitrogen atom to which they are bothattached form a heterocyclic ring optionally substituted with C₁₋₄alkyl;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In a fourth aspect, the present disclosure provides a compound ofFormula (III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of any of the first, second and thirdaspects, wherein:

R^(3b) is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—S(═O)_(p)R^(c),—S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5R⁵, and —(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substitutedwith 1-5 R⁵;

R^(3c) is independently selected from H and ═O;

R^(4a) is independently selected from H, F, Cl, Br, CN, OCH₃, OCF₃, CH₃,C(═O)C₁₋₄alkyl, C(═O)OC₁₋₄alkyl, CHF₂, CF₃, CCH₃F₂, OCHF₂,

R^(4b) is independently selected from H and F;

R^(4c) is independently selected from H, F, Cl, methyl, ethyl,isopropyl, and OCH₃;

R¹⁰, at each occurrence, is independently selected from H, F, Cl, Br,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with 0-5 R^(e), arylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with0-5 R^(e).

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e);

R^(b), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);

R^(c), at each occurrence, is C₁₋₆ alkyl substituted with 0-5 R^(e);

R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heterocyclyl, CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and—(CH₂)_(n)NR^(f)R^(f);

R^(f), at each occurrence, is independently selected from H, C₁₋₅ alkyloptionally substituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl;

n, at each occurrence, is an integer independently selected from 0, 1,2, 3, and 4; and

p, at each occurrence, is an integer independently selected from 0, 1,and 2.

In a fifth aspect, the present disclosure provides a compound of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, or a solvate thereof, within the scope of any of the first,second, third, and fourth aspects, wherein:

R^(3b) is independently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, —C(═O)NR^(a)R^(a), and−4- to 5-membered heterocyclyl substituted with 1-5 R⁵;

R^(3c) is independently selected from H and ═O;

is independently selected from

R⁵, at each occurrence, is independently selected from H,—C(═O)OC₁₋₄alkyl, OC₁₋₄alkyl;

R¹⁰, at each occurrence, is independently selected from H, F, Cl, Br,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with 0-5 R^(e), arylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with0-5 R^(e); and

n, at each occurrence, is an integer independently selected from 0, 1,2, and 3.

In a sixth aspect, the present disclosure provides a compound of Formula(IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of any of the first, second and thirdaspects, wherein:

R^(3b) is independently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, —C(═O)NR^(a)R^(a), and−4- to 5-membered heterocyclyl substituted with 1-5 R⁵;

R^(3c) is independently selected from H and ═O;

is independently selected from

R¹⁰, at each occurrence, is independently selected from H, F, Cl, Br,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with 0-5 R^(e), arylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with0-5 R^(e); and

n, at each occurrence, is an integer independently selected from 0, 1,2, and 3.

In a seventh aspect, the present disclosure provides a compound ofFormula (V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of any of the first, second, and thirdaspects, wherein:

R^(3b) is independently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, and −4- to 5-memberedheterocyclyl substituted with 1-5 R⁵;

R^(3c) is independently selected from H and ═O;

R^(4b) is independently selected from H and F;

R^(4c) is independently selected from H, F, Cl, methyl, ethyl,isopropyl, and OCH₃; R⁷ is independently selected from H and C₁₋₃ alkyl;and

n, at each occurrence, is an integer independently selected from 0, 1,2, and 3.

In an eighth aspect, the present disclosure provides a compound ofFormula (III), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst, second, and third aspects, wherein:

L is independently selected from

ring A is

R¹ and R² are independently selected from H, C₁₋₄ alkyl, and OH;

R³ is independently selected from —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a);

R^(3a) is H;

alternatively, R^(3a) and R³ are taken together to form a heterocyclicring selected from

R^(3b) is independently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, —C(═O)NR^(a)R^(a), and−4- to 6-membered heterocyclyl substituted with 1-5 R⁵;

R^(3c) is independently selected from H and ═O;

is independently selected from

R⁵, at each occurrence, is independently selected from H,—C(═O)OC₁₋₄alkyl, OC₁₋₄alkyl;

R⁷ is independently selected from H and C₁₋₃ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e);

R^(b), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);

R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, C₁₋₆ alkyl, haloalkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heterocyclyl, and CO₂H; and

n, at each occurrence, is an integer independently selected from 0, 1,2, and 3.

In a ninth aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the eighth aspect.

In another embodiment, the compounds of the present invention haveFactor XIa Ki values≤10 μM, using the assays disclosed herein,preferably, Ki values≤1 μM, more preferably, Ki values≤0.5 μM, even morepreferably, Ki values≤0.1 μM.

In another embodiment, the compounds of the present invention haveplasma kallikrein Ki values≤15 μM, using the assays disclosed herein,preferably, Ki values≤10 μM, more preferably, Ki values≤1.0 μM, evenmore preferably, Ki values≤0.5 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a factor Xa inhibitor such as apixaban, rivaroxaban,betrixaban, edoxaban, an anti-coagulant agent, an anti-platelet agent, athrombin inhibiting agent such as dabigatran, a thrombolytic agent, anda fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, desulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a method for theprophylaxis of a disease or condition in which plasma kallikreinactivity is implicated comprising administering to a patient in need ofsuch treatment and/or prophylaxis a therapeutically effective amount ofat least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

The disease or condition in which plasma kallikrein activity isimplicated includes, but not limited to, impaired visual acuity,diabetic retinopathy, diabetic macular edema, hereditary angioedema,diabetes, pancreatitis, nephropathy, cardio myopathy, neuropathy,inflammatory bowel disease, arthritis, inflammation, septic shock,hypotension, cancer, adult respiratory distress syndrome, disseminatedintravascular coagulation, and cardiopulmonary bypass surgery.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms. Alkyl group can be unsubstituted or substituted with atleast one hydrogen being replaced by another chemical group. Examplealkyl groups include, but are not limited to, methyl (Me), ethyl (Et),propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl,t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “amino,” as used herein, refers to —NH₂.

The term “substituted amino,” as used herein, refers to the definedterms below having the suffix “amino” such as “arylamino,” “alkylamino,”“arylamino,” etc.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylamino,” as used herein, refers to an —NHRwherein R is an alkoxycarbonyl group.

The term “alkylamino,” as used herein refers to —NHR, wherein R is analkyl group.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylcarbonylamino,” as used herein, refers to —NHR wherein Ris an alkylcarbonyl group.

The term “aminosulfonyl,” as used herein, refers to —SO₂NH₂.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups.

The term “arylamino,” as used herein, refers to —NHR wherein R is anaryl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “arylcarbonylamino,” as used herein refers to —NHR wherein R isan arylcarbonyl group.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkylamino,” as used herein, refers to —NHR wherein R isa cycloalkyl group.

The term “cycloalkylcarbonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “cycloalkylcarbonylamino,” as used herein, refers to —NHRwherein R is a cycloalkylcarbonyl group.

The term “cycloalkyloxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “dialkylamino,” as used herein, refers to NR₂, wherein each Ris an alkyl group. The two alkyl groups are the same or different.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “haloalkylamino,” as used herein, refers to —NHR wherein R is ahaloalkyl group.

The term “carbonyl” refers to C(═O).

The term “carboxy” refers to C(═O)OH.

The term “haloalkylcarbonyl,” as used herein, refers to a haloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “haloalkylcarbonylamino,” as used herein, refers to —NHRwherein R is a haloalkylcarbonyl group.

The terms “alkylcarbonyl” refer to an alkyl or substituted alkyl bondedto a carbonyl.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “hydroxy” or “hydroxyl” refers to OH.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or polycyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branchedcycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropylare included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclichydrocarbon ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Hawley'sCondensed Chemical Dictionary (13th Ed.), Lewis, R. J., ed., J. Wiley &Sons, Inc., New York (1997). “C₆ or C10 aryl” or

“C₆₋₁₀ aryl” refers to phenyl and naphthyl. Unless otherwise specified,“aryl”, “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may beunsubstituted or substituted with 1 to 5 groups, preferably 1 to 3groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

The term “benzyl” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N—O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,

1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,

5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,

1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” A    Textbook of Drug Design and Development, pp. 113-191,    Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat'd” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “8” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc or BOC tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   Cbz carbobenzyloxy-   DCM or CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   CuI copper(I) iodide-   CuSO₄ copper(II) sulfate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or Hunig's base diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs II    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    (phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂O₂ hydrogen peroxide-   H₂SO₄ sulfuric acid-   IBX 2-iodoxybenzoic acid-   InCl₃ Indium(III) chloride-   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium phosphate dibasic-   K₃PO₄ potassium phosphate tribasic-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NH₄COOH ammonium formate-   NMM N-methylmorpholine-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS Polystyrene-   rt room temperature-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   ®T3P propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane-   pTsOH p-toluenesulfonic acid

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis, which aredescribed in more detail in Section VI.

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, thrombosis in thecavity of the heart, ischemic stroke, deep vein thrombosis, peripheralocclusive arterial disease, transient ischemic attack, and pulmonaryembolism. In addition, thrombosis occurs on artificial surfaces incontact with blood, including catheters, stents, artificial heartvalves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Colman, R. W.et al., eds., Hemostasis and Thrombosis, Basic Principles and ClinicalPractice, 5th Edition, p. 853, Lippincott Williams & Wilkins (2006)).

Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in factor V (also known as factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of factor XII leads to a conformational change in the factorXII molecule, thereby facilitating activation to proteolytic activefactor XII molecules (factor XIIa and factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand factor XI. Active plasma kallikrein further activates factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of factor XIIdeficient mice. More specifically, factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that factor XI is down-stream from factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role infactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000)).

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001).) Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeC13)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. JPathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human factor XI protect against baboonarterial—venous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of factor XIa is also disclosed in published U.S. PatentPublication No. 2004/0180855 A1. Taken together, these studies suggestthat targeting factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding factor XII.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J. Med., 342:696-701 (2000)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, 2nd Edition, pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule factor XIa inhibitors in rabbit and rat model of arterialthrombosis, at doses that preserved hemostasis. (Wong P. C. et al.,American Heart Association Scientific Sessions, Abstract No. 6118, Nov.12-15, 2006; Schumacher, W. et al., Journal of Thrombosis andHaemostasis, 3(Suppl. 1):P1228 (2005); Schumacher, W. A. et al.,European Journal of Pharmacology, 167-174 (2007)). Furthermore, it wasobserved that in vitro prolongation of the aPTT by specific XIainhibitors is a good predictor of efficacy in our thrombosis models.Thus, the in vitro aPTT test can be used as a surrogate for efficacy invivo.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover a treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting a disease-state, i.e., arresting it development; and/or (b)relieving a disease-state, i.e., causing regression of a disease state.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Patients may be selected forprophylaxis therapy based on factors that are known to increase risk ofsuffering a clinical disease state compared to the general population.For prophylaxis treatment, conditions of the clinical disease state mayor may not be presented yet. “Prophylaxis” treatment can be divided into(a) primary prophylaxis and (b) secondary prophylaxis. Primaryprophylaxis is defined as treatment to reduce or minimize the risk of adisease state in a patient that has not yet presented with a clinicaldisease state, whereas secondary prophylaxis is defined as minimizing orreducing the risk of a recurrence or second occurrence of the same orsimilar clinical disease state.

As used herein, “prevention” covers the preventive treatment of asubclinical disease-state in a mammal, particularly in a human, aimed atreducing the probability of the occurrence of a clinical disease-state.Patients are selected for preventative therapy based on factors that areknown to increase risk of suffering a clinical disease state compared tothe general population.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from acute coronary syndrome,stroke, atrial fibrillation and venous thrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid intema, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl. JMed., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722(2005)). Hence, the most common cancers associated with thrombosis inmen are prostate, colorectal, brain, and lung cancer, and in women arebreast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., British Journal ofSurgery, 88:913-930 (2001).)

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikreinchymotrypsin, trypsin, or thrombin, can be determined using a relevantpurified serine protease, respectively, and an appropriate syntheticsubstrate. The rate of hydrolysis of the chromogenic or fluorogenicsubstrate by the relevant serine protease was measured both in theabsence and presence of compounds of the present invention. Hydrolysisof the substrate resulted in the release of pNA (para nitroaniline),which was monitored spectrophotometrically by measuring the increase inabsorbance at 405 nm, or the release of AMC (amino methylcoumarin),which was monitored spectrofluorometrically by measuring the increase inemission at 460 nm with excitation at 380 nm. A decrease in the rate ofabsorbance or fluorescence change in the presence of inhibitor isindicative of enzyme inhibition. Such methods are known to one skilledin the art. The results of this assay are expressed as the inhibitoryconstant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX® or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;CHROMOGENIX®) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 0.05 M HEPES buffer at pH 7.4containing 0.145 M NaCl, 0.05 M KCl, and 0.1% PEG 8000. Determinationswere made using purified human Factor XIIa at a final concentration of 4nM (American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human plasma kallikrein(Enzyme Research Laboratories) at a final assay concentration of 200 pMand the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX®)at a concentration of 0.00008-0.0004 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; CHROMOGENIX® or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. or 37° C. in the absence ofinhibitor. Values of K_(i) were determined by allowing the protease toreact with the substrate in the presence of the inhibitor. Reactionswere allowed to go for periods of 20-180 minutes (depending on theprotease) and the velocities (rate of absorbance or fluorescence changeversus time) were measured. The following relationships were used tocalculate K_(i) values:(V _(max) *S)/(K _(m) +S)(v _(o) −v _(s))/v _(s) =I/(K _(i)*(1+S/K _(m))) for a competitiveinhibitor with one binding site; orv _(s) /v _(o) =A+((B−A)/(1+(IC ₅₀/(I)^(n))); andK _(i) =IC ₅₀/(1+S/K _(m)) for a competitive inhibitorwhere:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

V_(max) is the maximum reaction velocity;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme: inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P=K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios >20are considered selective.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5× or IC2×, the inhibitor concentration requiredto increase the clotting time by 1.5 times or 2 times, respectively,relative to the clotting time in the absence of the inhibitor. TheIC1.5× or IC2× is found by linear interpolation from relative clottingtime versus inhibitor concentration plots using inhibitor concentrationsthat span the IC1.5× or IC2×.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g.,rat, or rabbit). A compound is diluted into plasma beginning with a 10mM DMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (Sysmex, Dade-Behring, Illinois). Similarly, clotting times canbe determined from laboratory animal species or humans dosed withcompounds of the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ACTIN®FSL (Dade-Behring, Illinois) following the directions in the packageinsert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute. ACTIN® FSL(0.05 mL) is added to the plasma and incubated for an additional 2 to 5minutes. Calcium chloride (25 mM, 0.05 mL) is added to the reaction toinitiate coagulation. The clotting time is the time in seconds from themoment calcium chloride is added until a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus or Innovin®, Dade-Behring, Illinois) following the directions inthe package insert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

Chymotrypsin determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human chymotrypsin at a final concentration of 0.2-2 nM(Calbiochem) and the synthetic substrate S-2586(Methoxy-Succinyl-Arg-Pro-Tyr-pNA; Chromogenix) at a concentration of0.0005-0.005 M.

Trypsin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human trypsin (Sigma) at a finalassay concentration of 0.1-1 nM and the synthetic substrate S-2222(Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA; Chromogenix) at aconcentration of 0.0005-0.005 M.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (Ki values) of ≤1.5 μM (1500 nM)was observed.

The exemplified Examples disclosed below were tested in the PlasmaKallikrein assay described above and found having Plasma Kallikreininhibitory activity. A range of Plasma Kallikrein inhibitory activity(Ki values) of ≤15 μM (15000 nM) was observed.

In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose that produces 50% inhibitionof thrombus formation) are estimated by a nonlinear least squareregression program using the Hill sigmoid E_(max) equation (DeltaGraph;SPSS Inc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient. In oneembodiment, the pharmaceutical composition is a solid formulation, e.g.,a spray-dried composition, which may be used as is, or whereto thephysician or the patient adds solvents, and/or diluents prior to use.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Soliddispersions are also called solid-state dispersions. In someembodiments, any compound described herein is formulated as a spraydried dispersion (SDD). An SDD is a single phase amorphous moleculardispersion of a drug in a polymer matrix. It is a solid solutionprepared by dissolving the drug and a polymer in a solvent (e.g.,acetone, methanol or the like) and spray drying the solution. Thesolvent rapidly evaporates from droplets which rapidly solidifies thepolymer and drug mixture trapping the drug in amorphous form as anamorphous molecular dispersion.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 300 milligrams per dosage unit,and the second anti-coagulant in an amount of about 1 to about 500milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 300 milligrams ofthe compound of the present invention and about 50 to about 150milligrams of the anti-platelet agent, preferably about 0.1 to about 4milligrams of the compound of the present invention and about 1 to about3 milligrams of antiplatelet agents, per kilogram of patient bodyweight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 100 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolytic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an antiarrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(alliskerin) and vasopepsidase inhibitors, an antiarrythmic agentselected from IKur inhibitors, an anticoagulant selected from thrombininhibitors, antithrombin-III activators, heparin co-factor IIactivators, other factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, factor VIIainhibitors, factor IXa inhibitors, and factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastro-intestinal tract in use. Clopidogrelis an even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, omithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent Factor XIa inhibitor of the present invention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry(Maffrand, J. P. et al., Heterocycles, 16(1):35-37 (1981)). Generalsynthetic schemes for preparing compounds of the present invention aredescribed below. These schemes are illustrative and are not meant tolimit the possible techniques one skilled in the art may use to preparethe compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

General Schemes

Representative pyrimidinone compounds Ic of this invention can beprepared as described in Scheme 1. Using a modified procedure describedby Xiao (Organic Letters, 11:1421 (2009)), suitably substitutedpyrimidin-4-ol derivatives 1b can be coupled with an appropriatelysubstituted macrocycle amine 1a in the presence of HATU and DBU in asolvent such as CH₃CN to provide pyrimidinone compounds 1c.

Representative dihydropyridone compounds 2f of this invention can beprepared as shown in Scheme 2. Starting from aldehyde 2a, vinyl Grignardaddition (yielding allylic alcohol 2b) followed by oxidation gives vinylketones 2c. Michael addition of the an appropriately substitutedmacrocycle amine 1a followed by acylation with 2d affords compounds 2e,which upon cyclization with base provides the dihydropyridone 2f.

Representative azole compounds 3b of this invention can be made as shownin Scheme 3 by coupling intermediates 3a and an appropriatelysubstituted macrocycle amine 1a using HATU and Hunig's base in DMF.

Representative macrocycle amine 4g of this invention can be made asshown in Scheme 4. Starting from 4a, coupling with 4b using copper (I)iodide and K₂CO₃ in DMSO to give 4c. Coupling 4c with 4d using T3P togive 4e which goes through GrubbII condition to form macrocycle 4f. Thedouble bond and protecting Cbz group can then be taken off underhydrogenation condition to provide macrocycle amine 4g.

In some cases the macrocycle amine bearing protecting groups such as Bocis coupled first using schemes 1 to 3 to afford R^(a). Then the Bocgroup is removed using HC₂ in dioxane to give 5b. Then various R^(3b)groups are installed to yield Hc.

Representative macrocycle amine 6h of this invention can be made asshown in Scheme 6. Starting from 6a, coupling with 6b using copper (I)iodide and CsF in DMSO to give 6c. Basic hydrolysis of 6c afforded 6d.Coupling 6d with 6e using T3P gave 6f which goes through GrubbIIreaction conditions to form macrocycle 6g. The double bond andprotecting Boc group can then be taken off under hydrogenation, thenacidic conditions, followed by free-basing to provide macrocycle amine6h.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using pre-packed SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc, DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% water, 10%MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% water, 10% ACN, 0.1% TFA) andSolvent B (10% water, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients ofSolvent A (98% water, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2%water, 0.05% TFA, UV 220 nm) (or) Sunfire Prep C18 OBD 5u 30×100 mm, 25min gradient from 0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA90:10:0.1

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A: Waters SunFire column (3.5 m C18, 3.0×150 mm). Gradientelution (0.5 mL/min) from 10-100% Solvent B for 12 min and then 100%Solvent B for 3 min was used. Solvent A is (95% water, 5% acetonitrile,0.05% TFA) and Solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV254 nm).

Method B: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min.

Method C: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B:95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.; Gradient:0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11mL/min

Method X: Phenomenex Luna 3u C18 column (2.0×50 mm). Gradient elution(0.8 mL/min) from 0-100% Solvent B for 4 min and then 100% Solvent B for2 min was used. Solvent A is (90% water, 10% MeOH, 0.1% TFA) and SolventB is (10% water, 90% MeOH, 0.1% TFA, UV 220 nm).

Intermediate 1. Preparation of tert-ButylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

1A. Preparation of(R)—N-[(1E)-(3-Bromophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromobenzaldehyde (7.8 g, 42.2 mmol) was added(R)-2-methylpropane-2-sulfinamide (5.11 g, 42.2 mmol), Cs₂CO₃ (20.60 g,63.2 mmol) in DCM (211 ml) and the resulting reaction mixture wasstirred for 5 days. The reaction mixture was then partitioned with brine(50 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (2×50ml). The combined organic layers were washed with brine (25 ml), dried(Na₂SO₄), filtered and concentrated. Purification by normal phasechromatography using hexanes and EtOAc as eluents gave(R)—N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide(11.8 g, 97%) as an amber oil. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H),8.02 (t, J=1.8 Hz, 1H), 7.74 (dt, J=7.7, 1.2 Hz, 1H), 7.64 (ddd, J=8.0,2.0, 1.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 1.34-1.22 (m, 9H). MS (ESI)m/z: 290 (M+H)⁺.

1B. Preparation of(R)—N-[(1S)-1-(3-Bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To (R)—N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide(11.8 g, 40.9 mmol) in THF (190 ml), in a 3 neck flask, cooled to 0° C.,was added allyl bromide (3.90 ml, 45.0 mmol) and In (6.58 g, 57.3 mmol).After stirred at rt for 18 h, the reaction was heated to 50° C. for 6 h,then stirred at rt for 18 h. The reaction mixture was filtered throughCelite® and the filtrate was quenched with water (100 ml). A thick cleargelatinous material formed in the aqueous layer. The organics wereextracted with EtOAc (4×75 ml).

The combined organic layer was washed with brine, dried with MgSO₄,filtered and concentrated to give(R)—N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamideas a clear oil (9.6 g, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (t, J=1.8Hz, 1H), 7.41 (dt, J=7.6, 1.6 Hz, 1H), 7.26-7.18 (m, 2H), 5.79-5.66 (m,1H), 5.23-5.16 (m, 2H), 4.46 (ddd, J=8.1, 5.6, 2.0 Hz, 1H), 3.69 (s,1H), 2.63-2.53 (m, 1H), 2.53-2.40 (m, 1H), 1.23-1.19 (m, 9H).

1C. Preparation of tert-ButylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

To(R)—N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(9.6 g, 29.1 mmol) in MeOH (300 ml) was added conc. HCl (4 ml). After 3h, the reaction was concentrated and the residue was dissolved in DCM(300 ml), cooled to 0° C., and then TEA (16.20 ml, 116 mmol) and Boc₂O(6.75 ml, 29.1 mmol) in DCM (20 ml) were added. After 18 h, additionalBoc₂O (1 g) was added and the reaction was stirred 4 h. The reaction wasquenched with water (100 ml) and extracted with DCM (3×50 ml). Thecombined organic layers were washed with brine (50 ml), dried (Na₂SO₄),filtered and concentrated. Purification by normal phase chromatographyusing hexanes and EtOAc as eluents gave tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (7.3 g, 77%) as a whitesolid. MS (ESI) m/z: 326.08 (M+H)⁺.

Intermediate 2. Preparation of benzyl(S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamate

To a round bottom flask was added (S)-tert-butyl(1-(3-bromophenyl)but-3-en-1-yl)carbamate, (5 g, 15.33 mmol), Dioxane(10 mL) and 4N HCl (7.66 mL, 30.7 mmol) in Dioxane. The reaction wasstirred at rt overnight. The reaction was concentrated and dried. To theresidue was added CH₂Cl₂ (30 mL), Hunig's Base (8.03 mL, 46.0 mmol) andCbz-C1 (2.188 mL, 15.33 mmol). The reaction was stirred at rt for 2 hr.The reaction was then diluted with CH₂Cl₂ (50 ml) and washed with water(50 ml) and brine (50 ml). The organic layer was dried over MgSO₄,filtered and concentrated. The resisue was purified using ISCO system(0-100% EtOAc/Hex gradient) to give (S)-benzyl(1-(3-bromophenyl)but-3-en-1-yl)carbamate (5.03 g, 13.96 mmol, 91%yield) as a white solid. MS (ESI) m/z: 360.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) 07.48-7.30 (m, 7H), 7.22 (d, J=5.0 Hz, 2H), 5.67 (ddt, J=17.1,10.1, 7.0 Hz, 1H), 5.21-5.05 (m, 5H), 4.79 (br. s., 1H), 2.65-2.39 (m,2H).

Intermediate 5. Preparation of6-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] pyrimidin-4-ol

5A. Preparation of 4-Chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl₂—CH₂Cl₂adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension waspurged with N₂, capped and heated at 80° C. for 22 h. The reaction wascooled to rt. Water was added to dissolve the salts, then the reactionwas filtered. The remaining solid was suspended in DCM and the insolublesolid was filtered. The filtrate was concentrated and then purified bynormal phase chromatography to give4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86%yield) as a white solid. MS (ESI) m/z: 172.3 (M-C₆H₁₀+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52(d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).

5B. Preparation of 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline

A RBF containing 4-chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol),4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62mmol), Na₂CO₃ (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) andwater (10.81 ml) was equipped with a condenser. The mixture was purgedwith Ar for several min then Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.77 g, 2.16mmol) was added. The reaction was heated at 90° C. for 5 h. The reactionwas cooled to rt, diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, concentrated and purified by normalphase chromatography to give 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline(2.86 g, 56.1% yield) as yellow solid. MS (ESI) m/z: 236.0 (M+H)⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.78 (d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H),7.15 (dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=1.1 Hz, 1H), 6.67 (d, J=8.8 Hz,1H), 5.89 (br. s., 2H), 4.03 (s, 3H).

5C. Preparation of4-{5-Chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g,6.36 mmol) in ACN (90 ml) at 0° C. was added 3-methylbutyl nitrite (1.28ml, 9.55 mmol), followed by the dropwise addition of TMSN₃ (1.26 ml,9.55 mmol). Gas evolution was observed. After 10 min, the ice bath wasremoved, and the reaction was allowed to warm to rt. After 1 h,ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu₂O (0.09 g, 0.64mmol) were added and the reaction was stirred for an additional 1 h. Thereaction was partitioned in EtOAc and sat NH₄Cl, and the layers wereseparated. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. Purification by normal phase chromatographygave4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(2.13 g, 5.92 mmol, 93% yield) as a yellow solid. MS(ESI) m/z: 360.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2Hz, 1H), 7.61-7.56 (m, 1H), 7.54-7.48 (m, 2H), 6.20 (d, J=1.1 Hz, 1H),3.92 (s, 3H), 0.32-0.28 (m, 9H).

5D. Preparation of4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.56 g, 4.33 mmol) in ACN (28.9 ml) wasadded NCS (2.03 g, 15.17 mmol) and silica gel (6.51 g, 108 mmol). Thereaction was stirred at 80° C. for 1 h. Then, the reaction was filteredto remove the silica gel and the collected silica gel was washed withEtOAc. The filtrate was washed with water (2×), brine and concentrated.Purification by normal phase chromatography gave4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(0.90 g, 64.5% yield) as a yellow foam. MS(ESI) m/z: 322.3 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (d, J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),7.66-7.55 (m, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98(s, 3H).

5E. Preparation of6-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

To a solution of4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine(900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% aq HBr (3 ml, 26.5mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and saturatedaqueous NaHCO3. The mixture was separated and the aqueous layer wasextracted with EtOAc (2×). The organic layers were combined,concentrated, and then the residue was purified by normal phasechromatography to give a white solid. The solid was suspended in Et₂O,filtered and washed with Et₂O to give6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] pyrimidin-4-ol(610 mg, 70.9% yield) as a white solid. MS(ESI) m/z: 308.3 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, J=8.5,2.3 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.44 (d, J=0.9 Hz, 1H).

Intermediate 6. Preparation of6-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

6A. Preparation of4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.0 g,4.24 mmol) in ACN (60.6 ml) at 0° C. was added 3-methylbutyl nitrite(0.86 ml, 6.36 mmol) followed by the dropwise addition of TMSN₃ (0.84ml, 6.36 mmol). Gas evolution was observed. After 10 min, the ice bathwas removed, and the reaction was allowed to warm to rt. After 2 h, Cu₂O(61 mg, 0.42 mmol) was added followed by a slow bubbling of3,3,3-trifluoroprop-1-yne gas over a period of 5 min. After anadditional 10 min, the reaction was partitioned between DCM and satNH₄Cl and then the layers were separated. The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated. Purification bynormal phase chromatography gave4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 97% yield) as a yellow solid. MS(ESI) m/z: 356.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (d, J=1.1 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.75(d, J=2.4 Hz, 1H), 7.66-7.60 (m, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.60 (d,J=1.1 Hz, 1H), 3.98 (s, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −61.10 (s).

6B. Preparation of6-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

To a solution of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine(1.46 g, 4.10 mmol) in AcOH (10 ml) was added 48% aq HBr (5 ml, 44.2mmol). The mixture was stirred at 85° C. for 1 h. The reaction wasconcentrated to dryness and then partitioned between EtOAc and satNaHCO₃. The layers were separated and the aqueous layer was extractedwith EtOAc (2×). The organic layers were combined and washed with satNaHCO₃, brine, dried over MgSO₄, filtered and the solvent was reducedunder vacuum until some solid started to form. The resulting suspensionwas triturated with Et₂O. The solid was filtered and washed with Et₂O togive6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol(1 g, 71.3% yield) as a pale yellow solid. MS(ESI) m/z: 342.0 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.83 (d, J=0.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H),7.87 (d, J=2.2 Hz, 1H), 7.79-7.72 (m, 1H), 7.70-7.62 (m, 1H), 6.45 (d,J=0.9 Hz, 1H). ¹⁹F NMR (376 MHz, CD₃OD) δ −62.61 (s).

Intermediate 7. Preparation of6-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

7A. Preparation of N-(4-Chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a suspension of 4-chloro-3-fluoroaniline (10.67 g, 73.3 mmol) andNa₂CO₃ (24.5 g, 125 mmol) in Et₂O (300 mL) at −10° C. under N₂ was addedTFAA (12.23 mL, 88 mmol) dropwise. The mixture was allowed to warm to rtand then stirred for 18 h. The reaction mixture was diluted with hexane(300 mL) and filtered. The filtrate was washed with ice-water, 10% aqNaHCO₃, and brine, dried over Na₂SO₄, and concentrated. A pale yellowsolid obtained as N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide(17 g, 96% yield). MS (ESI) m/z: 242.1 (M+H)⁺.

7B. Preparation of (6-Amino-3-chloro-2-fluorophenyl)boronic acid

To a cooled (−78° C.) clear, colorless solution ofN-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 20.70 mmol)in THF (69.0 ml) was added dropwise 2.5 M BuLi in hexane (16.56 ml, 41.4mmol) over 15 min, keeping the internal temperature below −60° C. Theresulting clear, yellow solution was stirred at −78° C. for 10 min, thenthe reaction was allowed to warm to −50° C. over 1 h. The resultingclear brown solution was cooled to −78° C. and then B(O-iPr)₃ (10.51 ml,45.5 mmol) was added dropwise. The reaction was stirred at −78° C. for10 min, and then the ice bath was removed and the reaction was allowedto warm to rt. The resulting orange suspension was stirred at rt for 2h, then cooled in ice bath and quenched with 1 N HCl (40 ml). Thereaction mixture was warmed to 40° C. for 1 h and then cooled to rt. Thereaction was diluted with EtOAc and the layers were separated. Theorganic layer was washed with brine and concentrated. Purification bynormal phase chromatography afforded(6-amino-3-chloro-2-fluorophenyl)boronic acid (3 g, 76.6% yield). MS(ESI) m/z: 190.1 (M+H)⁺.

7C. Preparation of 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

Reaction was done in a 350 ml pressure bottle. A solution of4-chloro-6-methoxypyrimidine (1.784 g, 12.34 mmol),(6-amino-3-chloro-2-fluorophenyl)boronic acid (3.3 g, 12.34 mmol) intoluene (25 ml) and EtOH (25 ml) was purged with N₂ for several min.DIEA (4.31 ml, 24.68 mmol) followed by Pd(Ph₃P)₄ (1.426 g, 1.234 mmol)were added. The flask was capped and the reaction was heated at 120° C.for 2 h, then cooled to rt, and concentrated. Purification by normalphase chromatography afforded4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 45.2% yield)as a yellow solid. MS (ESI) m/z: 254.0 (M+H)⁺.

7D. Preparation of4-(3-Chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear, yellow solution of4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2.1 g, 8.28 mmol)in ACN (118 ml) was added isoamyl nitrite (1.67 ml, 12.42 mmol),followed by the dropwise addition of TMSN₃ (1.63 ml, 12.42 mmol). After10 min, the cold bath was removed, and the reaction was allowed to warmto rt. After 2 h, ethynyltrimethylsilane (3.54 ml, 24.84 mmol) and Cu₂O(0.118 g, 0.83 mmol) were added, and the reaction was stirred at rt for1.5 h. The reaction was then diluted with EtOAc and washed with satNH₄Cl, brine, dried over MgSO₄, filtered and concentrated to give abrown oil. Purification by normal phase chromatography afforded4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(2.71 g, 87% yield) as a brown solid. MS (ESI) m/z: 378.1 (M+H)⁺.

7E. Preparation of4-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

In a RBF equipped with stirring bar and condenser was added4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine(2.71 g, 7.17 mmol), NCS (3.35 g, 25.1 mmol), and silica gel (10.77 g,179 mmol), followed by ACN (47.8 ml). The reaction was heated at 80° C.for 1 h, and then cooled to rt. The reaction was filtered, and thefiltrate was concentrated. The residue was redissolved in EtOAc andwashed with sat NaHCO₃, water, brine, and concentrated. Purification bynormal phase chromatography afforded4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(1.05 g, 43.0% yield) as a yellow solid. MS (ESI) m/z: 340.0 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.68 (d, J=0.7 Hz, 1H), 7.71-7.62 (m, 2H), 7.37(dd, J=8.6, 1.8 Hz, 1H), 6.84 (s, 1H), 4.02 (s, 3H).

7F. Preparation of6-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

A clear, yellow solution of4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine(1.05 g, 3.09 mmol) in HOAc (15.43 ml) and 48% aq HBr (17.46 ml, 154mmol) was warmed to 65° C. for 3 h, and then cooled to rt andconcentrated. The yellow gum was suspended in EtOAc and washed with satNaHCO₃ (2×), brine, dried over Na₂SO₄, filtered, and concentrated. Tothe residue was added Et₂O (10 ml), and the resulting suspension wassonicated then filtered. The solid was rinsed with Et₂O (2 ml),air-dried with suction to afford6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol(0.79 g, 78% yield) as a white solid. MS (ESI) m/z: 326.3 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.08 (d, J=0.7 Hz, 1H), 7.85 (dd,J=8.7, 7.6 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 6.57 (s, 1H).

Intermediate 8. Preparation of1-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

8A. Preparation of 2-Azido-5-chlorobenzaldehyde

A solution of 5-chloro-2-fluorobenzaldehyde (1.38 g, 8.70 mmol) andsodium azide (0.58 g, 8.92 mmol) in DMF (4 mL) was stirred at 55° C. for8 h then cooled to rt. The reaction mixture was diluted with diethylether and water which was then acidified with 1N HCl to pH 4. Theetheral layer was washed with water (3×) followed by brine (3×), thendried over MgSO₄ and filtered. The organic layers were then concentratedunder vacuum to yield 1.47 g of 2-azido-5-chlorobenzaldehyde (93%) aspale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.30 (s, 1H), 7.86 (d,J=2.6 Hz, 1H), 7.58 (dd, J=8.7, 2.5 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H)

8B. Preparation of5-Chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde

A solution of 2-azido-5-chlorobenzaldehyde (386 mg, 2.126 mmol) andtributylstanylacetylene (0.646 mL, 2.126 mmol) in toluene (5 mL) washeated at 100° C. for 5 h before cooling down to rt. After 5 h, thereaction mixture was concentrated and directly purified using normalphase chromatography to yield 495 mg of5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (43%)as pale yellow oil. MS (ESI) m/z: 498.1 (M+H)+.

8C. Preparation of5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde

To a solution of5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (459mg, 0.924 mmol) in ACN (5 mL) was added N-chlorosuccinimide (185 mg,1.386 mmol) and the reaction was then heated at 60° C. for 15 h. After15 h, the reaction mixture was concentrated and directly purified usingnormal phase chromatography to yield 117 mg of5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde (52%) as whitesolid. MS (ESI) m/z: 242.0 (M+H, Chlorine isotope peak)+.

8D. Preparation of1-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

1-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one wasprepared using a procedure analogous to that used for the preparation ofIntermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde. MS (ESI) m/z:268.3 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.66 (m, 1H), 7.62-7.52 (m,2H), 7.44 (d, J=8.4 Hz, 1H), 6.29 (dd, J=17.6, 10.6 Hz, 1H), 5.98-5.79(m, 2H).

Intermediate 11. Preparation of1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

11A. Preparation of Ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate

A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517g, 2.79 mmol), (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.500g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) wasstirred at rt. After 10 min, the reaction mixture was concentrated andpurified by silica gel chromatography. The desired product, ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (200 mg,28%), was obtained as an off white solid. MS(ESI) m/z: 283.1 (M+H)⁺.

Intermediate 11. Preparation of1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

To a solution of ethyl1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (50 mg,0.177 mmol) in MeOH (0.884 mL) was added 1 N NaOH (aqueous) (1.061 mL,1.061 mmol) and the reaction was stirred at 50° C. in a sealed vial for3 h. The reaction mixture was then cooled to rt and concentrated. Theresidue was then partitioned between 1 N HCl and EtOAc. The layers wereseparated and the aqueous layer was extracted with EtOAc. The organiclayers were combined, washed with brine, and concentrated to giveIntermediate 25 as an off-white solid (48 mg, 107%). MS(ESI) m/z: 255.0(M+H)⁺.

Intermediate 13 Preparation of5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

13A. Preparation of Ethyl5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate

To a mixture of (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.67g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol)and sodium acetate (0.586 g, 7.12 mmol) at room temperature was addedAcOH and H₂O to form a slurry. The reaction mixture was continued tostir at room temperature for 0.25 h and then heated at 100° C.overnight. After overnight stirring, the reaction mixture was quenchedwith H₂O (200 mL) and a yellowish brown solid separated. The solids werefiltered and washed thoroughly with H₂O. R^(e)-dissolved the residue inDCM, dried and evaporated to a brown solid as the desired product (0.76g, 78%). MS (ESI) m/z: 284.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s,1H), 7.51-7.29 (m, 2H), 7.27-7.03 (m, 1H), 5.30-5.06 (m, 2H), 4.24 (q,J=7.2 Hz, 2H), 1.38-1.04 (m, 3H) ppm.

13B

To acetonitrile (7 ml) was added butylnitrite (0.381 ml, 3.25 mmol)followed by CuCl2 (0.437 g, 3.25 mmol). After stirring for 0.5 h thepyrazole ethyl5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate (0.615 g,2.168 mmol) in acetonitile (3 ml) was added dropwise via a syringe. Thereaction mixture was subsequently stirred at rt for 2 h. Quenched withwater (100 ml) and extracted organics with EtOAc (2×100 ml), dried(MgSO₄) and evaporated to a yellow oil. Purified via 40 g silica gelISCO column and eluted with Hex/EtOAc. Pure product eluted at approx 20%EtOAc. Concentrated to a yellowish-brown oil (0.61 g, 93%). LCMS m/z303.0 (M+H).

13. Preparation of5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid

Intermediate 13B (0.61 g, 2.01 mmol) was dissolved in THF (10 ml) and tothis solution was added sequentially LiOH (0.2 g) and methanol (5 ml)and water added (7 ml). the reaction mixture was allowed to stir at rtfor 2 h. Quenched with dil HCl (1N, 100 ml) and extracted organics withEtOAc (2×100 ml), dried and evaporated to a white solid. Purified viaprep HPLC to afford the desired product as a white solid (0.26 g, 46%).LCMs m/z=275.1 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1H),7.53-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.23-7.19 (m, 1H).

Example 1. Preparation of tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

1A. Preparation of (S)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate

To a sealed tube was added tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate, prepared as describedin intermediate 2, (S)-benzyl (1-(3-bromophenyl)but-3-en-1-yl)carbamate(0.8 g, 2.221 mmol), (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (0.562 g, 2.443 mmol), K₂CO₃ (0.921 g, 6.66 mmol) and DMSO (2.22ml). The reaction was purged with Ar and then CuI (0.021 g, 0.111 mmol)was added. The reaction was sealed and stirred at 110° C. overnight. Thereaction was partitioned between water (40 ml) and EtOAc (50 ml). Theorganic layer was separated, washed with saturated aqueous NH₄Cl (40ml), water (40 ml), and brine (40 ml). The layers were separated and theorganic layer was dried over MgSO₄, filtered and concentrated to givecrude(S)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid as a greenish gum. Then to this crude material was added EtOAc (5mL), but-3-en-1-amine (112 mg, 1.57 mmol), and pyridine (0.254 mL, 3.14mmol) followed by addition of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1 g,1.570 mmol). The reaction was stirred at rt overnight. The reaction wasdiluted with EtOAc (30 ml) and the reaction was washed with saturatedaqueous NaHCO₃ (20 ml), water (30 ml) and brine (30 ml). The organiclayer was separated, dried over MgSO₄, filtered and concentrated. Theresidue was purified using ISCO system (0-100% EtOAc/Hex gradient) togive (S)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate(180 mg, 0.320 mmol, 20.4% yield) as a white solid. (ESI) m/z: 563.4(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (br. s., 4H), 7.27-7.23 (m, 1H),6.85 (d, J=7.7 Hz, 1H), 6.73 (d, J=6.2 Hz, 2H), 6.65 (br. s., 1H),5.78-5.54 (m, 2H), 5.21-5.06 (m, 5H), 5.03-4.92 (m, 2H), 4.76 (br. s.,1H), 4.23-4.10 (m, 1H), 3.99 (br. s., 1H), 3.78-3.64 (m, 2H), 3.55 (ddd,J=13.0, 9.7, 3.6 Hz, 1H), 3.49-3.42 (m, 1H), 3.41-3.23 (m, 3H),2.62-2.44 (m, 2H), 2.24-2.09 (m, 2H), 1.52-1.48 (m, 9H).

1B. Preparation of tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate

To a RBF was added (S)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate(170 mg, 0.302 mmol) and DCE (40 mL). The reaction was purged with Arfor 5 min and then Grubbs II (103 mg, 0.121 mmol) was added and thereaction was stirred at 50° C. under Ar for 5 h. The reaction wasconcentrated and purified using ISCO system (0-100% EtOAc/Hex gradient)to give tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate (150 mg, 0.281 mmol, 93% yield) asa light colored solid. (ESI) m/z: 535.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 7.43-7.32 (m, 5H), 7.30-7.27 (m, 4H), 6.90-6.82 (m, 2H), 6.60 (s, 1H),6.04 (br. s., 1H), 5.58-5.47 (m, 1H), 5.29 (br. s., 1H), 4.95-4.83 (m,1H), 4.79 (br. s., 1H), 4.04 (t, J=4.5 Hz, 1H), 3.74 (d, J=5.5 Hz, 1H),3.62 (br. s., 2H), 3.41-3.25 (m, 3H), 3.05 (br. s., 1H), 2.54 (br. s.,1H), 2.45 (br. s., 2H), 2.20-2.05 (m, 1H), 1.50 (s, 9H).

1C. Preparation of tert-butyl(7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a 3-neck RBF was added tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate (150 mg, 0.281 mmol), EtOH (5 mL) andPd/C (59.7 mg, 0.056 mmol). The reaction was stirred under hydrogenballoon for 2 h. The reaction was then carefully filtered through theCelite. The filtrate was concentrate to give tert-butyl(7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (110 mg, 0.286 mmol, 99% yield) as a lightcolored solid. (ESI) m/z: 403.2 (M+H)⁺.

Example 1. Predation of tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added6-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-olprepared as described in intermediate 5,(6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol)(97 mg, 0.314 mmol), ACN (5 mL), HATU (141 mg, 0.371 mmol) and DBU(0.065 mL, 0.429 mmol). The suspension turned into a solution after DBUwas added. The reaction was stirred at rt for 10 min. Then tert-butyl(7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate(115 mg, 0.286 mmol) was added and the reaction was stirred at rtovernight. The reaction was purified using RP prep-HPLC to givetert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate(115 mg, 0.166 mmol, 58.0% yield) as a beige solid. (ESI) m z: 693.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (br. s., 1H), 7.70 (s, 1H), 7.68(d, J=2.2 Hz, 1H), 7.61 (dd, J=8.5, 2.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H),7.37-7.31 (m, 1H), 7.04 (d, J=9.5 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.85(br. s., 1H), 6.53 (br. s., 1H), 6.44 (s, 1H), 5.78 (dd, J=12.1, 3.1 Hz,1H), 4.02 (br. s., 2H), 3.87 (d, J=13.2 Hz, 2H), 3.68-3.59 (m, 2H),3.56-3.47 (m, 2H), 3.35 (br. s., 1H), 1.98 (dd, J=8.0, 4.7 Hz, 1H),1.92-1.78 (m, 1H), 1.50 (s, 11H), 1.43 (d, J=6.4 Hz, 3H), 1.11 (br. s.,1H). Analytical HPLC (Method X) RT=3.788 min, purity=96%. Factor XIaKi=955 nM, Plasma Kallikrein Ki=3473 nM.

Example 2. Preparation of(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride

To a RBF was added tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (110 mg, 0.159 mmol), dioxane (1 mL) and 4 NHCl in dioxane (0.145 mL, 4.76 mmol). The reaction was stirred at rt for30 min. The reaction was concentrated to give(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one hydrochloride (85 mg, 0.125 mmol, 79% yield) as abeige solid. (ESI) m/z: 593.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.76 (d,J=19.1 Hz, 1H), 8.40-8.36 (m, 1H), 7.91-7.87 (m, 1H), 7.78-7.75 (m, 1H),7.70-7.66 (m, 1H), 7.45-7.39 (m, 1H), 7.24-7.18 (m, 2H), 6.94 (d, J=7.5Hz, 1H), 6.41 (s, 1H), 5.60 (d, J=12.3 Hz, 1H), 4.37-4.28 (m, 1H),3.85-3.74 (m, 2H), 3.72-3.66 (m, 2H), 3.63-3.38 (m, 5H), 2.78-2.67 (m,1H), 2.42-2.26 (m, 1H), 2.15-2.05 (m, 1H), 1.68-1.56 (m, 1H), 1.49 (br.s., 2H), 1.01 (dt, J=13.8, 7.0 Hz, 1H). Analytical HPLC (Method X)RT=2.880 min, purity=95%. Factor XIa Ki=542 nM, Plasma KallikreinKi=7292 nM.

Example 3. Preparation of methyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride (13 mg, 0.021 mmol), Et₃N (14.38 μl, 0.103 mmol), THF (0.5ml) and methyl carbonochloridate (2.145 mg, 0.023 mmol). The reactionwas stirred at rt for 10 min. The reaction was concentrated, thendissolved in MeOH and purified using RP Prep-HPLC to give methyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (10.7 mg, 0.016 mmol, 76% yield) as a beigesolid. (ESI) m/z: 651.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s,1H), 8.46 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.81(dd, J=8.4, 2.3 Hz, 1H), 7.75-7.70 (m, 1H), 7.21-7.16 (m, 1H), 7.01 (s,1H), 6.93 (d, J=8.5 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.44 (s, 1H), 5.71(dd, J=12.8, 3.4 Hz, 1H), 4.24 (br. s., 1H), 3.84 (dd, J=13.3, 4.4 Hz,1H), 3.77-3.72 (m, 1H), 3.68 (dd, J=13.4, 4.0 Hz, 1H), 3.61 (br. s.,3H), 3.55-3.49 (m, 1H), 2.93 (d, J=13.1 Hz, 1H), 2.63 (d, J=13.7 Hz,2H), 1.62 (br. s., 1H), 1.53 (br. s., 3H), 1.31-1.12 (m, 5H). AnalyticalHPLC (Method C) RT=1.689 min, purity=95%. Factor XIa Ki=643 nM, PlasmaKallikrein Ki=4111 nM.

Examples 4 and 5. Preparation of tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylateand tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

4A. Preparation of (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate

To a RBF was added (R)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoicacid (2.6 g, 10.91 mmol) and MeOH (50 mL). The reaction was cooled to 0°C. Then SOCl₂ (5.58 mL, 76 mmol) was added dropwise over 10 min and thereaction was slowly warmed to rt and stirred at rt overnight. Thereaction was concentrated to give (R)-methyl3-amino-2-(((benzyloxy)carbonyl)amino)propanoate hydrochloride (3.15 g,10.91 mmol, 100% yield) as a white solid. Then to this solid was addedTHF (40 mL) and Hunig's Base (5.72 mL, 32.7 mmol). The solution wasstirred at rt for 10 min then benzyl 2-bromoacetate (3.46 mL, 21.82mmol) was added. The reaction was stirred at rt for 4 h. The reactionwas partitioned between water (40 ml) and EtOAc (60 ml). The organiclayer was separated, washed with water (2×40 ml) and brine (2×40 ml),dried over MgSO₄, filtered and concentrated. The residue was purifiedusing ISCO system (0-100% EtOAc/Hex gradient) to give (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate(1.92 g, 4.79 mmol, 43.9% yield) as a clear oil. (ESI) m/z: 401.1(M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.33 (m, 10H), 5.78 (d, J=7.2 Hz,1H), 5.20-5.13 (m, 4H), 4.56-4.39 (m, 1H), 3.77 (s, 3H), 3.50-3.39 (m,2H), 3.15 (dd, J=12.4, 4.7 Hz, 1H), 3.00 (dd, J=12.5, 4.3 Hz, 1H).

4B. Preparation of (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate

To a RBF was added (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate(3.19 g, 7.97 mmol), THF (40 mL), Hunig's Base (4.17 mL, 23.90 mmol),followed by BOC-Anhydride (3.70 mL, 15.93 mmol). The reaction wasstirred at rt overnight. The reaction was partitioned between EtOAc (50ml) and water (40 ml). The organic layer was separated, washed withwater (40 ml) and brine (40 ml), dried over MgSO₄, filtered andconcentrated. The residue purified using ISCO system (0-60% EtOAc/Hexgradient) to give (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate(2.25 g, 4.50 mmol, 56.4% yield) as a clear oil. (ESI) m/z: 501.1(M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.30 (m, 10H), 6.17-5.69 (m, 1H),5.23-5.05 (m, 4H), 4.64-4.42 (m, 1H), 4.00-3.91 (m, 2H), 3.87-3.79 (m,1H), 3.77-3.52 (m, 4H), 1.49-1.35 (m, 9H).

4C. Preparation of(R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)aceticacid

To a 3 neck RBF was added (R)-methyl3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate(2.25 g, 4.50 mmol), EtOH (30 mL) and Pd/C (0.024 g, 0.225 mmol). Thereaction was stirred under an atmosphere of hydrogen (balloon) for 2 h.The reaction was carefully filtered and the filtrate was concentrated togive(R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)aceticacid (850 mg, 3.08 mmol, 68.4% yield) as a white solid. (ESI) m/z: 277.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 4.34 (dd, J=9.7, 4.4 Hz, 1H), 3.91(dd, J=14.9, 4.3 Hz, 1H), 3.87-3.85 (m, 3H), 3.83-3.72 (m, 1H),3.70-3.60 (m, 1H), 1.51-1.41 (m, 9H).

4D. Preparation of (R)-1-tert-butyl 3-methyl5-oxopiperazine-1,3-dicarboxylate

To a RBF was added(R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)aceticacid (850 mg, 3.08 mmol) and CH₂Cl₂ (100 mL). The reaction was cooled to0° C. and DCC (952 mg, 4.61 mmol) was added. The reaction was stirred inan ice-water bath for 4 h then Et₃N (0.858 mL, 6.15 mmol) was added tothe reaction and the reaction was stirred at rt over the weekend. Thereaction was concentrated and the residue was stirred in EtOAc (50 ml).The suspension was filtered and the filtrate was concentrated. Theresidue was purified using ISCO system (0-100% EtOAc/Hex gradient) togive (R)-1-tert-butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate (700mg, 2.71 mmol, 88% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ6.43 (br. s., 1H), 4.30-4.00 (m, 4H), 3.90-3.80 (m, 3H), 3.70 (d, J=7.5Hz, 1H), 1.53-1.44 (m, 9H).

4E. Preparation of (R)-1-tert-butyl 3-methyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-1,3-dicarboxylate

To a RBF was added tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.65 g, 1.804 mmol), (R)-1-tert-butyl 3-methyl5-oxopiperazine-1,3-dicarboxylate (0.699 g, 2.71 mmol), CsF (1.370 g,9.02 mmol), THF (3.61 ml) and N,N′-dimethylethylene diamine (0.039 ml,0.361 mmol). The reaction was purged with Ar and then CuI (0.034 g,0.180 mmol) was added and the reaction was capped and stirred at rt for2 days. The reaction was partitioned between EtOAc (40 ml) and water (20ml). The organic layer was separated, washed with saturated aqueousNH₄Cl (30 ml), water (30 ml) and brine (30 ml), dried over MgSO₄,filtered and concentrated. The residue was purified using ISCO system(0-100% EtOAc/Hex gradient) to give (R)-1-tert-butyl 3-methyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-1,3-dicarboxylate(280 mg, 0.521 mmol, 28.9% yield) as a white solid. (ESI) m/z: 538.2(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.29 (m, 6H), 7.25 (d, J=7.5 Hz,1H), 7.19 (d, J=7.3 Hz, 2H), 5.79-5.61 (m, 1H), 5.20-5.02 (m, 5H), 4.83(br. s., 1H), 4.62 (d, J=18.0 Hz, 2H), 4.38 (br. s., 1H), 4.02 (d,J=18.7 Hz, 1H), 3.77-3.69 (m, 3H), 3.53 (d, J=10.3 Hz, 1H), 2.65-2.43(m, 2H), 1.50 (s, 9H).

4F. Preparation of (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate

To a RBF was added (R)-1-tert-butyl 3-methyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-1,3-dicarboxylate(280 mg, 0.521 mmol) and THF (5 mL). Then LiOH.H₂O (22.95 mg, 0.547mmol) in water (1 mL) was added to the reaction and the reaction wasstirred at rt for 2 h. The reaction was concentrated to give(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylicacid (270 mg, 0.516 mmol, 99% yield) as a lithium salt. To this materialwas added(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylicacid (270 mg, 0.516 mmol), THF (5 mL), Hunig's Base (0.270 mL, 1.547mmol), but-3-en-1-amine (73.4 mg, 1.031 mmol) and HATU (392 mg, 1.031mmol). The reaction was stirred at rt for 4 h. The reaction waspartitioned between EtOAc (50 ml) and water (30 ml). The organic layerwas separated, washed with water (30 mL) and brine (30 ml), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate(280 mg, 0.486 mmol, 94% yield) as a white solid. (ESI) m/z: 577.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.32 (m, 5H), 7.25-7.11 (m, 3H),5.79-5.58 (m, 2H), 5.24-5.04 (m, 6H), 4.80 (br. s., 1H), 4.64-4.35 (m,2H), 4.32-4.16 (m, 1H), 4.09 (d, J=17.8 Hz, 1H), 3.61 (d, J=13.4 Hz,1H), 3.30 (br. s., 2H), 2.68-2.42 (m, 2H), 2.27-2.10 (m, 2H), 1.57-1.45(m, 10H).

4G. Preparation of tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylateand tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate

To a RBF was added (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate(275 mg, 0.477 mmol) and DCE (50 mL). The reaction was purged with Arfor 5 min and then Grubbs II (121 mg, 0.143 mmol) was added and thereaction was stirred at 50° C. under Ar for 2 h. The reaction wasconcentrated and purified using ISCO system (0-100% EtOAc/Hex gradient)to give a mixture of tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate and tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate(200 mg, 0.365 mmol, 76% yield) as a light colored solid. (ESI) m/z:549.1 (M+H)⁺.

4H. Preparation of tert-butyl(7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylateand tert-butyl(7S,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a 2-neck RBF was added a mixture of tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylateand tert-butyl(7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate(190 mg, 0.346 mmol), EtOH (10 mL) and Pd/C (73.7 mg, 0.069 mmol). Thereaction was stirred under an atmosphere of hydrogen (balloon) for 2 h.The reaction was carefully filtered through Celite and the filtrate wasconcentrated to give a mixture of tert-butyl(7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate and tert-butyl(7S,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (140 mg, 0.336 mmol, 97% yield) as a beigesolid. (ESI) m/z: 417.4 (M+H)⁺.

Example 4 and 5. Preparation of tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylateand tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (110mg, 0.357 mmol), ACN (3 ml), HATU (160 mg, 0.421 mmol) and DBU (73.3 μl,0.486 mmol). The suspension turned into a solution after DBU was added.The reaction was stirred at rt for 10 min. Then a mixture of tert-butyl(7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate and tert-butyl(7S,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate(135 mg, 0.324 mmol) was added and the reaction was stirred at rtovernight. The reaction was purified using RP prep-HPLC. Two diasteomerswere separated. The peak that eluted out first (that had shorterretention time) was tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (62 mg, 0.083 mmol, 25.7% yield). (ESI) m/z:707.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.33 (s, 1H), 8.07(d, J=7.3 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.78-7.72 (m, 1H), 7.69-7.64(m, 1H), 7.54-7.48 (m, 1H), 7.39-7.32 (m, 2H), 7.23 (d, J=7.0 Hz, 1H),6.45 (s, 1H), 5.72 (dd, J=11.7, 3.3 Hz, 1H), 4.66-4.44 (m, 1H),4.33-4.01 (m, 3H), 3.91-3.83 (m, 1H), 3.67 (d, J=11.0 Hz, 1H), 2.91 (br.s., 1H), 2.31-2.19 (m, 1H), 2.18-2.05 (m, 1H), 1.63 (d, J=10.3 Hz, 1H),1.51 (br. s., 9H), 1.43-1.34 (m, 4H), 1.13 (br. s., 1H). Analytical HPLC(Method X) RT=3.563 min, purity=95%. Factor XIa Ki=9020 nM, PlasmaKallikrein Ki=3136 nM. The peak that eluted second (that had longerretention time) was tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (62 mg, 0.083 mmol, 25.7% yield). (ESI) m/z:707.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.42-8.30 (m, 3H), 7.89-7.85 (m,1H), 7.76-7.70 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 1H), 7.43(s, 1H), 7.40-7.36 (m, 1H), 7.33 (d, J=7.5 Hz, 1H), 6.38 (d, J=0.4 Hz,1H), 5.85 (dd, J=12.4, 3.0 Hz, 1H), 4.69-4.44 (m, 1H), 4.31-3.99 (m,3H), 3.93-3.78 (m, 1H), 3.64 (br. s., 1H), 2.88 (br. s., 1H), 2.47 (dt,J=13.0, 6.6 Hz, 1H), 1.90 (dd, J=13.4, 3.1 Hz, 2H), 1.51 (br. s., 10H),1.44-1.38 (m, 1H), 1.33 (d, J=7.0 Hz, 3H). Analytical HPLC (Method X)RT=3.633 min, purity=95%. Factor XIa Ki=276 nM, Plasma KallikreinKi=6001 nM.

Example 6. Preparation of(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-3,8-dionehydrochloride

To a RBF was added tert-butyl(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate,prepared as described in Example 4 (62 mg, 0.088 mmol) and MeOH (0.5mL), followed by 4 N HCl in dioxane (0.266 mL, 8.76 mmol). The reactionwas stirred at rt for 15 min. The reaction was concentrated to give(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-3,8-dione hydrochloride salt (40 mg, 0.059 mmol, 67.3%yield) as an off-white solid. (ESI) m/z: 607.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.71 (s, 1H), 8.40-8.32 (m, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.88(d, J=2.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.71-7.65 (m, 1H), 7.63-7.53 (m,1H), 7.44-7.29 (m, 3H), 6.41 (s, 1H), 5.64 (dd, J=12.3, 3.5 Hz, 1H),4.49 (br. s., 1H), 4.24-4.04 (m, 2H), 3.89 (d, J=3.5 Hz, 2H), 3.76-3.59(m, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.36-2.12 (m, 2H), 1.66-1.51 (m, 1H),1.47-1.42 (m, 1H), 1.14-1.01 (m, 1H), 0.71-0.48 (m, 1H). Analytical HPLC(Method X) RT=2.735 min, purity=95%. Factor XIa Ki=6004 nM, PlasmaKallikrein Ki=13020 nM.

Example 7. Preparation of(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-3,8-dionehydrochloride

To a RBF was added tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate, prepared as described in Example 5 (62 mg,0.088 mmol) and MeOH (0.5 mL), followed by 4 N HCl in dioxane (0.266 mL,8.76 mmol). The reaction was stirred at rt for 15 min. The reaction wasconcentrated to give(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-3,8-dione hydrochloride (40 mg, 0.059 mmol, 67.3% yield) asan off-white solid. (ESI) m/z: 607.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.65-8.54 (m, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.86 (d, J=2.2 Hz, 1H),7.77-7.70 (m, 1H), 7.67-7.61 (m, 1H), 7.60-7.54 (m, 1H), 7.52-7.46 (m,2H), 7.41 (d, J=8.1 Hz, 1H), 6.36 (s, 1H), 5.84 (dd, J=12.3, 2.6 Hz,1H), 4.46-4.40 (m, 1H), 4.22-4.09 (m, 2H), 3.92-3.87 (m, 2H), 3.80-3.57(m, 9H), 2.74-2.57 (m, 2H), 2.02-1.83 (m, 2H), 1.68-1.55 (m, 2H),1.35-1.30 (m, 1H), 1.05-0.91 (m, 1H). Analytical HPLC (Method X)RT=2.806 min, purity=95%. Factor XIa Ki=97 nM, Plasma Kallikrein Ki=4780nM.

Example 8. Preparation of tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

8A. Preparation of(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid

To a sealed tube was added tert-ButylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate, prepared as describedin intermediate 2 (1 g, 2.78 mmol),(R)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (0.767 g, 3.33mmol), K₂CO₃ (1.151 g, 8.33 mmol) and DMSO (2.78 ml). The reaction waspurged with Ar and then CuI (0.026 g, 0.139 mmol) was added. Thereaction was sealed and stirred at 110° C. for 30 h. The reaction waspartitioned between water (40 ml) and EtOAc (50 ml). The organic layerwas separated, washed with saturated aqueous NH₄Cl (40 ml), water (40ml) and brine (40 ml), dried over MgSO₄, filtered and concentrated togive crude mixture as greenish gum. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (400 mg, 0.785 mmol, 28.3% yield) as a white solid. (ESI) m/z:510.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.30 (m, 5H), 7.23 (d,J=7.0 Hz, 1H), 6.87-6.71 (m, 3H), 5.68 (br. s., 1H), 5.19-4.99 (m, 5H),4.76 (br. s., 1H), 4.66-4.33 (m, 2H), 4.16-3.99 (m, 1H), 3.59-3.47 (m,1H), 3.39 (br. s., 2H), 3.16 (br. s., 1H), 2.54 (br. s., 2H), 1.48 (s,9H).

8B. Preparation of (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate

To a RBF was added(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (220 mg, 0.432 mmol), THF (5 mL), Hunig's Base (0.226 mL, 1.295mmol), but-3-en-1-amine (61.4 mg, 0.864 mmol) and HATU (328 mg, 0.863mmol). The reaction was stirred at rt for 3 h. The reaction waspartitioned between EtOAc (50 ml) and water (30 ml). The organic layerwas separated, washed with water (30 ml) and brine (30 ml), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate(220 mg, 0.391 mmol, 91% yield) as a white solid. (ESI) m/z: 563.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (br. s., 4H), 7.27-7.23 (m, 1H),6.85 (d, J=7.5 Hz, 1H), 6.79-6.70 (m, 2H), 6.62 (br. s., 1H), 5.78-5.49(m, 2H), 5.22-5.03 (m, 5H), 5.03-4.90 (m, 2H), 4.77 (d, J=5.5 Hz, 1H),4.13 (dd, J=13.4, 4.4 Hz, 1H), 3.99 (br. s., 1H), 3.72 (d, J=12.8 Hz,2H), 3.60-3.22 (m, 5H), 2.62-2.45 (m, 2H), 2.24-2.06 (m, 2H), 1.50 (s,9H), 1.34-1.24 (m, 1H).

8C. Preparation of tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate

To a RBF was added (R)-tert-butyl4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate(220 mg, 0.391 mmol) and DCE (40 mL). The reaction was purged with Arfor 5 min and then Grubbs II (66.4 mg, 0.078 mmol) was added and thereaction was stirred at 50° C. under Ar for 5 h. The reaction wasconcentrated and purified using ISCO system (0-100% EtOAc/Hex gradient)to give tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate (170 mg, 0.318 mmol, 81% yield) as alight colored solid. (ESI) m/z: 535.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.44-7.30 (m, 6H), 6.85 (dd, J=8.3, 1.9 Hz, 1H), 6.81 (d, J=7.0 Hz, 1H),6.51 (br. s., 1H), 5.95 (br. s., 1H), 5.47-5.35 (m, 1H), 5.28 (br. s.,1H), 5.16-5.07 (m, 2H), 4.86 (dt, J=14.3, 7.2 Hz, 1H), 4.66 (br. s.,1H), 4.25-4.10 (m, 1H), 4.05 (br. s., 1H), 3.76 (br. s., 1H), 3.62 (br.s., 2H), 3.53 (d, J=8.1 Hz, 1H), 3.44-3.36 (m, 1H), 3.33 (br. s., 1H),2.88 (br. s., 1H), 2.66-2.50 (m, 2H), 2.21-2.12 (m, 1H), 2.08 (dd,J=13.9, 4.8 Hz, 1H), 1.51 (s, 9H).

8D. Preparation of tert-butyl(7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate

To a 2-neck RBF was added tert-butyl(7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),12,16,18-tetraene-5-carboxylate (165 mg, 0.309 mmol), EtOH (10 mL)and Pd/C (65.7 mg, 0.062 mmol). The reaction was stirred under anatmosphere of hydrogen (balloon) for 2 h. The reaction was carefullyfiltered through Celite and the filtrate was concentrated to givetert-butyl(7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate (120 mg, 0.298 mmol, 97% yield) as a beigesolid. (ESI) m/z: 403.2 (M+H)⁺.

Example 8. Preparation of tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added6-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,prepared as described in intermediate 5, ACN (5 mL), HATU (147 mg, 0.388mmol) and DBU (0.067 mL, 0.447 mmol). The suspension turned into asolution after DBU was added. The reaction was stirred at rt for 10 min.Then tert-butyl(7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate (120 mg, 0.298 mmol) was added and thereaction was stirred at rt overnight. The reaction was purified using RPprep-HPLC to give tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (50 mg, 0.068 mmol, 22.97% yield) as a beigesolid. (ESI) m/z: 693.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.71-8.65 (m,1H), 8.35 (s, 1H), 8.25 (d, J=6.8 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H),7.79-7.72 (m, 1H), 7.69-7.65 (m, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.09-6.99(m, 2H), 6.57 (d, J=7.3 Hz, 1H), 6.44-6.37 (m, 1H), 5.70 (dd, J=13.0,2.6 Hz, 1H), 4.17 (t, J=5.0 Hz, 1H), 3.89-3.52 (m, 6H), 3.23 (br. s.,1H), 2.93 (d, J=13.2 Hz, 1H), 2.40-2.24 (m, 1H), 2.03-1.89 (m, 1H),1.88-1.73 (m, 2H), 1.66-1.54 (m, 1H), 1.49 (s, 9H), 1.38-1.29 (m, 1H),1.26-1.18 (m, 1H), 1.12 (d, J=12.3 Hz, 1H). Analytical HPLC (Method X)RT=3.758 min, purity=95%. Factor XIa Ki=21 nM, Plasma Kallikrein Ki=1087nM.

Example 9. Preparation of(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride

To a RBF was added tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate,prepared as described in Example 8 (50 mg, 0.072 mmol), MeOH (0.5 mL),dioxane (1 mL) and 4 N HCl in dioxane (1.802 mL, 7.21 mmol). Thereaction was stirred at rt for 15 min. The reaction was concentrated togive(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one hydrochloride (40 mg, 0.062 mmol, 85% yield) as abeige solid. (ESI) m/z: 593.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.81-8.74 (m, 1H), 8.42-8.36 (m, 1H), 7.93-7.84 (m, 2H), 7.80-7.72 (m,1H), 7.69-7.59 (m, 1H), 7.44-7.34 (m, 1H), 7.22-7.13 (m, 2H), 7.04 (d,J=7.7 Hz, 1H), 6.45 (s, 1H), 5.68 (dd, J=12.8, 2.9 Hz, 1H), 4.26 (t,J=3.9 Hz, 1H), 3.93-3.81 (m, 1H), 3.79-3.56 (m, 5H), 3.44-3.38 (m, 1H),2.66-2.47 (m, 2H), 2.05-1.87 (m, 1H), 1.68-1.49 (m, 2H), 1.48-1.36 (m,2H), 1.05 (dd, J=8.0, 3.9 Hz, 1H), 0.97-0.83 (m, 1H). Analytical HPLC(Method X) RT=2.883 min, purity=97%. Factor XIa Ki=11 nM, PlasmaKallikrein Ki=1821 nM.

Example 10. Preparation of methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride, prepared as described in Example 9 (12 mg, 0.019 mmol),THF (0.5 mL), Et₃N (0.013 mL, 0.095 mmol), and methyl carbonochloridate(1.800 mg, 0.019 mmol). The reaction was stirred at rt for 2 h. Thereaction was purified using RP prep-HPLC to give methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate(6 mg, 8.75 μmol, 45.9% yield) as a beige solid. (ESI) m/z: 651.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.37-8.34 (m, 1H), 7.89(d, J=2.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.69-7.65 (m, 1H), 7.31 (t, J=7.9Hz, 1H), 7.08-6.99 (m, 2H), 6.59 (d, J=7.7 Hz, 1H), 6.42 (d, J=0.7 Hz,1H), 5.70 (dd, J=13.0, 2.6 Hz, 1H), 4.18 (br. s., 1H), 3.91 (dd, J=13.6,4.2 Hz, 1H), 3.77-3.69 (m, 6H), 3.63-3.56 (m, 1H), 3.55-3.45 (m, 1H),3.27-3.16 (m, 1H), 2.97-2.84 (m, 1H), 2.39-2.24 (m, 1H), 2.00-1.90 (m,1H), 1.85-1.72 (m, 2H), 1.62-1.53 (m, 1H), 1.38-1.27 (m, 1H), 1.22 (t,J=12.0 Hz, 1H), 1.13 (t, J=12.3 Hz, 1H). Analytical HPLC (Method A)RT=7.666 min, purity=95%. Factor XIa Ki=5 nM, Plasma Kallikrein Ki=862nM.

Example 11. Preparation of tert-butyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetatetrifluoromethylacetate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride, prepared as described in Example 9 (18 mg, 0.029 mmol),K₂CO₃ (19.74 mg, 0.143 mmol), THF (0.5 mL) and tert-butyl 2-bromoacetate(6.69 mg, 0.034 mmol). The reaction was stirred at rt for 5 h. Then Et₃N(30 ul) and DMF (0.3 ml) were added and the reaction was stirred at rtovernight. The reaction was purified using RP prep-HPLC to givetert-butyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetatetrifluoromethylacetate (14 mg, 0.017 mmol, 57.8% yield) as a whitesolid. (ESI) m/z: 707.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H),8.40 (s, 1H), 7.96 (br. s., 1H), 7.87 (d, J=2.4 Hz, 1H), 7.77-7.71 (m,1H), 7.67-7.61 (m, 1H), 7.42-7.35 (m, 1H), 7.22-7.15 (m, 2H), 7.10 (d,J=7.3 Hz, 1H), 6.47 (s, 1H), 5.67 (dd, J=12.8, 2.6 Hz, 1H), 4.29 (t,J=3.4 Hz, 1H), 4.04-3.94 (m, 1H), 3.86 (d, J=9.0 Hz, 1H), 3.74 (d,J=11.9 Hz, 1H), 3.67 (dd, J=12.2, 3.2 Hz, 2H), 3.58-3.47 (m, 1H),3.42-3.36 (m, 1H), 2.67-2.46 (m, 2H), 1.92 (t, J=11.0 Hz, 1H), 1.66-1.49(m, 12H), 1.34 (d, J=7.5 Hz, 1H), 1.01 (d, J=8.1 Hz, 1H), 0.71 (br. s.,1H). Analytical HPLC (Method A) RT=6.613 min, purity=97%. Factor XIaKi=11 nM, Plasma Kallikrein Ki=460 nM.

Example 12. Preparation of(7R,15S)-5-acetyl-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride, prepared as described in Example 9 (12 mg, 0.019 mmol),THF (0.5 mL), Et₃N (0.013 mL, 0.095 mmol) and acetyl chloride (1.495 mg,0.019 mmol). The reaction was stirred at rt for 2 h. The reaction waspurified using RP prep-HPLC system to give(7R,15S)-5-acetyl-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one(6 mg, 8.97 μmol, 47.1% yield) as a white solid. (ESI) m/z: 635.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.73-8.60 (m, 1H), 8.35 (s, 1H), 7.89(s, 1H), 7.77-7.73 (m, 1H), 7.68 (s, 1H), 7.36-7.27 (m, 1H), 7.09-6.99(m, 2H), 6.64-6.52 (m, 1H), 6.44-6.38 (m, 1H), 5.75-5.66 (m, 1H),4.28-4.14 (m, 1H), 4.03-3.56 (m, 6H), 3.55-3.44 (m, 1H), 3.02-2.82 (m,1H), 2.38-2.23 (m, 1H), 2.15 (d, J=8.8 Hz, 3H), 2.01-1.89 (m, 1H),1.87-1.73 (m, 2H), 1.65-1.51 (m, 1H), 1.43-1.05 (m, 3H). Analytical HPLC(Method A) RT=6.898 min, purity=95%. Factor XIa Ki=6 nM, PlasmaKallikrein Ki=1053 nM.

Example 13. Preparation of(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-methyl-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one,trifluoromethyl acetate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride, prepared as described in Example 9 (12 mg, 0.019 mmol),DCM (0.5 mL), AcOH (5.45 μl, 0.095 mmol), paraformaldehyde (5.72 mg,0.190 mmol) and sodium triacetoxyborohydride (6.06 mg, 0.029 mmol). Thereaction was stirred at rt overnight. HPLC showed starting material wasstill left so an additional amount of paraformaldehyde (5.72 mg, 0.190mmol) and sodium triacetoxyborohydride (6.06 mg, 0.029 mmol) were addedand the reaction was stirred at rt for additional 5 h. The reactionmixture was concentrated and purified using RP prep-HPLC to give(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-methyl-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one trifluoromethylacetate (6.5 mg, 8.83 μmol, 46.3%yield) as a white solid. (ESI) m/z: 607.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.72 (s, 1H), 8.40-8.38 (m, 1H), 7.90-7.85 (m, 1H), 7.78-7.73(m, 1H), 7.68-7.63 (m, 1H), 7.43-7.36 (m, 1H), 7.21-7.14 (m, 2H), 7.09(br. s., 1H), 6.45 (s, 1H), 5.67 (dd, J=12.8, 2.9 Hz, 1H), 4.29 (br. s.,1H), 4.02-3.47 (m, 6H), 3.38 (br. s., 1H), 3.01 (s, 3H), 2.71-2.38 (m,2H), 1.95 (d, J=11.2 Hz, 1H), 1.69-1.23 (m, 4H), 1.04 (br. s., 1H),0.76-0.51 (m, 1H). Analytical HPLC (Method A) RT=5.256 min, purity=98%.Factor XIa Ki=10 nM, Plasma Kallikrein Ki=441 nM.

Example 14. Preparation of2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]aceticacid trifluoromethyl acetate

To a RBF was added tert-butyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetatetrifluoromethylacetate, prepared as described in Example 11 (14 mg,0.020 mmol), CH₂Cl₂ (0.2 mL) and TFA (0.152 mL, 1.978 mmol). Thereaction was stirred at rt overnight. The reaction concentrated and theresidue purified using RP prep-HPLC to give2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetic acid trifluoromethylacetate (8 mg, 9.93 μmol,50.2% yield) as a white solid. (ESI) m/z: 651.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.72 (s, 1H), 8.39-8.37 (m, 1H), 7.99-7.90 (m, 1H), 7.87 (d,J=2.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.67-7.63 (m, 1H), 7.43-7.37 (m, 1H),7.21-7.16 (m, 2H), 7.11 (d, J=7.5 Hz, 1H), 6.46 (d, J=0.7 Hz, 1H), 5.68(dd, J=12.8, 2.9 Hz, 1H), 4.30 (t, J=3.5 Hz, 1H), 4.18 (d, J=2.0 Hz,2H), 4.04-3.96 (m, 1H), 3.88 (d, J=11.7 Hz, 1H), 3.78 (d, J=12.1 Hz,1H), 3.72 (dd, J=12.3, 3.5 Hz, 1H), 3.69-3.63 (m, 1H), 3.60-3.52 (m,1H), 3.42-3.36 (m, 1H), 2.65-2.50 (m, 2H), 1.97-1.89 (m, 1H), 1.68-1.49(m, 3H), 1.37 (br. s., 1H), 1.11-0.95 (m, 1H), 0.74 (br. s., 1H).Analytical HPLC (Method A) RT=5.321 min, purity=95%. Factor XIa Ki=5 nM,Plasma Kallikrein Ki=107 nM.

Example 15. Preparation of tert-butyl(7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate,trifluoromethylacetate

Example 15A. Preparation of (R)-tert-butyl3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate

To a RBF was added(R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylicacid prepared as described in Example 8A (220 mg, 0.432 mmol), THF (3mL), Et₃N (0.120 mL, 0.863 mmol), prop-2-en-1-amine (49.3 mg, 0.863mmol) and HATU (328 mg, 0.863 mmol). The reaction was stirred at rt for3 h. The reaction was partitioned between EtOAc (50 ml) and water (30ml). The organic layer was separated, washed with water (30 mL) andbrine (30 ml), dried over MgSO₄, filtered and concentrated. The residuewas purified using ISCO system (0-100% EtOAc/Hex gradient) to give(R)-tert-butyl3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate(170 mg, 0.310 mmol, 71.8% yield) as a white solid. (ESI) m/z: 549.3(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (br. s., 5H), 7.30-7.24 (m, 1H),6.86 (d, J=7.7 Hz, 1H), 6.77 (d, J=6.6 Hz, 2H), 6.66 (br. s., 1H),5.77-5.58 (m, 2H), 5.24-4.92 (m, 7H), 4.76 (br. s., 1H), 4.14 (dd,J=13.3, 4.5 Hz, 1H), 4.03 (br. s., 1H), 3.85 (t, J=5.2 Hz, 2H),3.80-3.67 (m, 2H), 3.60-3.45 (m, 2H), 3.42-3.30 (m, 1H), 2.59-2.42 (m,2H), 1.52-1.46 (m, 9H), 1.36-1.30 (m, 1H).

Example 15B. Preparation of tert-butyl(7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),11,15,17-tetraene-5-carboxylate

To a RBF was added (R)-tert-butyl3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate,prepared as described in Example 15A (150 mg, 0.273 mmol) and DCE (30mL). The reaction was purged with Ar for 5 min and then Grubbs II (46.4mg, 0.055 mmol) was added and the reaction was stirred at 50° C. underAr for 5 h. The reaction was concentrated and purified using ISCO system(0-100% EtOAc/Hex gradient) to give tert-butyl(7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),11,15,17-tetraene-5-carboxylate(55 mg, 0.106 mmol, 38.6% yield) as a light colored solid. (ESI) m/z:521.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.51-7.21 (m, 5H), 7.13-6.93 (m,2H), 6.87-6.72 (m, 1H), 6.58 (br. s., 1H), 5.83-5.63 (m, 1H), 5.17-4.94(m, 2H), 4.70 (dd, J=16.1, 8.6 Hz, 2H), 4.08 (d, J=13.2 Hz, 1H),4.03-3.90 (m, 1H), 3.66-3.40 (m, 3H), 3.02-2.91 (m, 1H), 2.52-2.27 (m,2H), 2.18 (d, J=19.1 Hz, 1H), 1.57-1.37 (m, 9H).

Example 15C. Preparation of tert-butyl(7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate

To a 3-neck RBF was added tert-butyl(7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),11,15,17-tetraene-5-carboxylateprepared as described in Example 15B (53 mg, 0.102 mmol), EtOH (5 mL)and Pd/C (10.83 mg, 10.18 μmol). The reaction was stirred under anatmosphere of hydrogen (balloon) for 3 h. The reaction was carefullyfiltered through Celite. The filtrate was concentrated to givetert-butyl(7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate(25 mg, 0.064 mmol, 63.2% yield) as an off-white solid. (ESI) m/z: 389.2(M+H)⁺.

Example 15. Preparation of tert-butyl(7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylatetrifluoromethylacetate

To a RBF was added6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-olprepared in intermediate 5 (21.81 mg, 0.071 mmol), ACN (1 mL), HATU(31.8 mg, 0.084 mmol) and DBU (0.015 mL, 0.097 mmol). The suspensionturned into a solution after DBU was added. The reaction was stirred atrt for 10 min. Then tert-butyl(7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate (25 mg, 0.064 mmol) was added and thereaction was stirred at rt overnight. The reaction was purified using RPprep-HPLC to give tert-butyl(7R,14S)-14-{4-[5-chloro-2-(4-chloro-TH-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate,trifluoromethyl acetate (12 mg, 0.014 mmol, 22.32% yield) as a beigesolid. (ESI) m/z: 679.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H),8.38-8.35 (m, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.78-7.73 (m, 1H), 7.68-7.63(m, 1H), 7.36-7.28 (m, 1H), 7.19 (br. s., 1H), 7.10 (dd, J=8.3, 2.1 Hz,1H), 6.63 (d, J=7.5 Hz, 1H), 6.44 (s, 1H), 5.70 (dd, J=11.8, 3.2 Hz,1H), 4.10-3.97 (m, 1H), 3.91 (d, J=10.8 Hz, 1H), 3.81 (dd, J=8.5, 3.6Hz, 1H), 3.70-3.55 (m, 2H), 3.52-3.42 (m, 2H), 3.13 (d, J=9.0 Hz, 1H),2.89 (d, J=12.5 Hz, 1H), 2.14-2.06 (m, 1H), 2.02-1.94 (m, 1H), 1.60-1.54(m, 1H), 1.50 (s, 9H), 1.45-1.29 (m, 3H). Analytical HPLC (Method A)RT=12.616 min, purity=95%. Factor XIa Ki=492 nM, Plasma KallikreinKi=3432 nM.

Example 16. Preparation of(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-(oxetan-3-yl)-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onetrifluoromethylacetate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride prepared as described in Example 9 (10 mg, 0.016 mmol),DCM (0.5 mL), AcOH (4.54 μl, 0.079 mmol), oxetan-3-one (11.44 mg, 0.159mmol) and sodium triacetoxyborohydride (33.6 mg, 0.159 mmol). Thereaction was stirred at rt overnight. The reaction mixture wasconcentrated and the residue purified using RP prep-HPLC to give(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-(oxetan-3-yl)-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onetrifluoromethylacetate (6.5 mg, 8.09 μmol, 50.9% yield) as a whitesolid. (ESI) m/z: 649.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.74-8.65 (m,1H), 8.40-8.31 (m, 1H), 8.03 (br. s., 1H), 7.91-7.84 (m, 1H), 7.79-7.72(m, 1H), 7.70-7.61 (m, 1H), 7.43-7.33 (m, 1H), 7.23-7.11 (m, 2H),7.04-6.94 (m, 1H), 6.46-6.39 (m, 1H), 5.68 (dd, J=12.9, 3.0 Hz, 1H),4.99-4.90 (m, 2H), 4.89-4.82 (m, 4H), 4.56-4.47 (m, 1H), 4.34-4.25 (m,1H), 3.93-3.78 (m, 1H), 3.67-3.56 (m, 2H), 3.55-3.47 (m, 1H), 3.45-3.38(m, 1H), 2.80-2.63 (m, 1H), 2.58-2.43 (m, 1H), 1.96 (dd, J=12.7, 10.0Hz, 1H), 1.69-1.46 (m, 3H), 1.42-1.30 (m, 1H), 1.09 (br. s., 2H).Analytical HPLC (Method A) RT=8.049 min, purity=95%. Factor XIa Ki=13nM, Plasma Kallikrein Ki=528 nM.

Example 17. Preparation of ethyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]-1,3-oxazole-5-carboxylatetrifluoromethylacetate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride prepared as described in Example 9 (12 mg, 0.019 mmol),DMF (0.2 mL), Et₃N (0.013 mL, 0.095 mmol) and ethyl2-chlorooxazole-5-carboxylate (6.69 mg, 0.038 mmol). The reaction wasstirred at 80° C. overnight. The reaction was purified using RPprep-HPLC to give ethyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]-1,3-oxazole-5-carboxylate trifluoromethyl acetate (5mg, 5.61 μmol, 29.5% yield) as a light brown solid. (ESI) m/z: 732.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.36 (s, 1H), 8.31 (d,J=8.1 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.69-7.65 (m,1H), 7.64-7.59 (m, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.12-7.03 (m, 2H), 6.62(d, J=7.7 Hz, 1H), 6.42 (s, 1H), 5.71 (dd, J=13.0, 2.4 Hz, 1H), 4.33 (q,J=7.2 Hz, 3H), 4.29-4.23 (m, 1H), 4.09-4.01 (m, 1H), 3.97-3.82 (m, 3H),3.73-3.63 (m, 1H), 3.55-3.44 (m, 1H), 2.94-2.84 (m, 1H), 2.38-2.27 (m,1H), 2.00-1.90 (m, 1H), 1.84-1.71 (m, 2H), 1.63-1.54 (m, 1H), 1.36 (t,J=7.2 Hz, 5H), 1.23 (d, J=6.8 Hz, 1H), 1.12 (d, J=12.3 Hz, 1H).Analytical HPLC (Method A) RT=12.214 min, purity=95%. Factor XIa Ki=16nM, Plasma Kallikrein Ki=1218 nM.

Example 18. Preparation of tert-butyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate,trifluoromethylacetate

To a RBF was added tert-butyl(7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate, prepared as described in Example 8D (17 mg,0.036 mmol),1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid,prepared as in intermediate 11 (9.10 mg, 0.036 mmol), HATU (20.39 mg,0.054 mmol). Hunig's Base (0.031 mL, 0.179 mmol) and DMF (0.5 mL). Thereaction was stirred at rt for 1 h. The reaction was diluted with MeOHand a few drops of water and purified using RP prep-HPLC system. Thedesired product was concentrated to give tert-butyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylatetrifluoromethyl acetate (15 mg, 0.019 mmol, 53.5% yield) as an-off-white solid. (ESI) m/z: 639.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.30 (d, J=6.8 Hz, 1H), 8.25 (s, 1H), 7.73 (ddd, J=8.3, 6.7, 1.8 Hz,1H), 7.48 (ddd, J=8.1, 6.5, 1.7 Hz, 1H), 7.44-7.30 (m, 2H), 7.12-6.99(m, 3H), 5.01 (dd, J=10.6, 5.3 Hz, 1H), 4.21 (dd, J=7.5, 4.0 Hz, 1H),3.68-3.57 (m, 3H), 3.56-3.44 (m, 2H), 3.24 (br. s., 1H), 2.90 (d, J=13.6Hz, 1H), 2.39 (d, J=0.9 Hz, 3H), 1.89 (td, J=9.7, 5.0 Hz, 2H), 1.84-1.68(m, 2H), 1.59-1.52 (m, 1H), 1.50 (s, 10H), 1.26-1.11 (m, 2H), 1.02-0.86(m, 1H). Analytical HPLC (Method X) RT=3.770 min, purity=95%. Factor XIaKi=3314 nM, Plasma Kallikrein Ki=3827 nM.

Example 19. Preparation of tert-butyl(7R,15S)-15-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylatetrifluoromethylacetate

(7R,15S)-15-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate, trifluoromethylacetate (4 mg, 4.51 μmol,22.67% yield) was prepared in a similar manner as the proceduredescribed in Example 1, by replacing(6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol)with6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol,prepared as described in Intermediate 7. (ESI) m/z: 711.6 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=6.6 Hz, 1H),7.91-7.85 (m, 1H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H),7.07-6.97 (m, 2H), 6.63 (s, 1H), 6.51 (d, J=7.5 Hz, 1H), 5.71 (dd,J=13.0, 2.6 Hz, 1H), 4.17 (br. s., 1H), 3.94-3.49 (m, 8H), 2.94 (d,J=11.9 Hz, 1H), 2.34-2.25 (m, 1H), 1.97 (t, J=11.8 Hz, 1H), 1.87-1.76(m, 2H), 1.63-1.56 (m, 1H), 1.49 (s, 9H), 1.37-1.08 (m, 4H). AnalyticalHPLC (Method A) RT=12.844 min, purity=95%. Factor XIa Ki=5 nM, PlasmaKallikrein Ki=345 nM.

Example 20. Preparation of1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamidehydrochloride

To a RBF was added tert-butyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate, trifluoromethylacetate prepared as describedin Example 18 (13 mg, 0.020 mmol) and 4 N HCl in dioxane (0.254 mL,1.017 mmol). The reaction was stirred at rt for 1 h. The reaction wasconcentrated to give1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide, hydrochloride (10 mg,0.017 mmol, 81% yield) as a white solid. (ESI) m/z: 539.2 (M+H)⁺.Analytical HPLC (Method A) RT=7.801 min, purity=95%. Factor XIa Ki=1306nM, Plasma Kallikrein Ki=2550 nM.

Example 21. Preparation of methyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate,trifluoromethyl acetate

To a RBF was added1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide hydrochloride prepared asdescribed in Example 20 (15 mg, 0.025 mmol), Et₃N (0.017 mL, 0.123 mmol)and THF (0.5 mL) followed by methyl chloroformate (2.278 μl, 0.029mmol). The reaction was stirred at rt for 10 min. The reaction wasdiluted with MeOH and purified using RP prep-HPLC to give(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate, trifluoromethylacetate (5 mg, 6.61 μmol,27.0% yield) as an off-white solid. (ESI) m/z: 597.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.44-8.37 (m, 1H), 8.31 (br. s., 1H), 7.90-7.76 (m, 2H),7.60-7.42 (m, 3H), 7.25-7.09 (m, 3H), 5.22-5.09 (m, 2H), 4.32-4.14 (m,2H), 4.01-3.94 (m, 1H), 3.93-3.87 (m, 3H), 3.83-3.62 (m, 4H), 3.28 (d,J=8.6 Hz, 1H), 3.09 (br. s., 1H), 2.63-2.53 (m, 3H), 2.09-1.82 (m, 4H),1.68 (br. s., 1H), 1.33 (br. s., 2H), 1.09 (d, J=11.2 Hz, 1H).Analytical HPLC (Method A) RT=11.019 min, purity=94%. Factor XIa Ki=1059nM, Plasma Kallikrein Ki=9168 nM.

Example 22. Preparation of methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylatetrifluoromethyl acetate

22A. Preparation of tert-butyl(7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}-2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate

To a RBF was added tert-butyl(7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate prepared as described in Example 8D (15 mg,0.032 mmol), DCM (1.5 mL), and DIEA (0.039 mL, 0.221 mmol) followed by1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-oneprepared in intermediate 8,1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one(8.46 mg, 0.032 mmol). The reaction was stirred at rt for 50 min. Thereaction was then cooled to 0° C. and pyridine (0.013 mL, 0.158 mmol)was added followed by 2-(diethoxyphosphoryl)acetic acid (18.56 mg, 0.095mmol). Then POCl₃ (5.88 μl, 0.063 mmol) was added dropwise and thereaction was stirred at 0° C. for 10 min. The reaction was then dilutedwith CH₂Cl₂ (15 ml) and washed with saturated aqueous NaHCO₃ (10 ml).The organic layer was separated, washed with water (10 ml) and brine (10ml), dried over MgSO₄, filtered and concentrated. The residue waspurified using ISCO system (0-30% MeOH/CH₂Cl₂ gradient) to givetert-butyl(7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}-2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (25 mg, 0.029 mmol, 93% yield) as a lightbrown solid. (ESI) m/z: 848.3 (M+H)⁺.

22B. Preparation of tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylatetrifluoromethylacetate

To a RBF was added tert-butyl(7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}-2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate (28 mg, 0.033 mmol) and MeOH (0.5 mL). Thereaction was cooled to 0° C. and then NaOMe (21.39 mg, 0.099 mmol) wasadded and the reaction was stirred at 0° C. for 30 min. The reaction wasthen neutralized with 1 N HCl (0.066 mL, 0.066 mmol). The reaction wasdiluted with MeOH and purified using RP prep-HPLC to give tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate,trifluoromethylacetate (15 mg, 0.019 mmol, 56.2% yield) as a brown film.(ESI) m/z: 694.7 (M+H)⁺.

22C. Preparation of(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride

To a RBF was added tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate, trifluoromethylacetate (15 mg, 0.019 mmol)and 4 N HCl in dioxane (0.232 mL, 0.927 mmol) and MeOH (0.2 mL). Thereaction was stirred at rt for 1 h. The reaction was concentrated togive(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one, hydrochloride (10 mg, 0.016 mmol, 85% yield) as abeige solid. (ESI) m/z: 594.2 (M+H)⁺.

Example 22. Preparation of methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylatetrifluoromethyl acetate

To a RBF was added(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-onehydrochloride (15 mg, 0.022 mmol), THF (0.5 mL), Et₃N (0.016 mL, 0.112mmol) followed by methyl chloroformate (2.61 μl, 0.034 mmol). Thereaction was stirred at rt for 10 min. The reaction was diluted withMeOH and purified using RP prep-HPLC to give methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate trifluoromethyl acetate (5 mg, 6.39 μmol,28.4% yield) as a white solid. (ESI) m/z: 652.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.49-8.44 (m, 1H), 8.22 (d, J=4.8 Hz, 1H), 7.69-7.57 (m, 3H),7.34-7.27 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J=7.5Hz, 1H), 5.80 (s, 1H), 5.40 (dd, J=12.3, 3.1 Hz, 1H), 4.07 (br. s., 1H),3.94 (dd, J=13.5, 4.1 Hz, 1H), 3.76-3.68 (m, 8H), 3.57 (dd, J=11.4, 4.0Hz, 1H), 3.43 (d, J=12.3 Hz, 1H), 3.19 (ddd, J=11.7, 7.3, 4.1 Hz, 1H),2.93-2.77 (m, 1H), 2.37-2.22 (m, 2H), 2.16-2.04 (m, 1H), 1.79-1.50 (m,4H), 1.35-1.25 (m, 1H), 1.23-1.12 (m, 1H), 1.09-0.93 (m, 1H). AnalyticalHPLC (Method A) RT=11.641 min, purity=98%. Factor XIa Ki=5 nM, PlasmaKallikrein Ki=189 nM.

Example 23. Preparation of methylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamatetrifluoromethyl acetate

23A. Preparation of(R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino)-3-((tert-butoxycarbonyl)amino)propanoicacid

To a sealed tube was added intermediate 2, (S)-benzyl(1-(3-bromophenyl)but-3-en-1-yl)carbamate (1, 2.78 mmol),(R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid (680 mg, 3.33mmol), K₂CO₃ (1151 mg, 8.33 mmol) and DMSO (5552 μl). The reaction waspurged with argon and then CuI (26.4 mg, 0.139 mmol) was added. Thereaction was sealed and stirred at 110° C. for 30 h. The reaction waspartitioned between water (40 ml) and EtOAc (50 ml). The organic layerwas separated, washed with saturated aqueous NH₄Cl (40 ml), water (40ml) and brine (40 ml), dried over MgSO₄, filtered and concentrated togive(R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino)-3-((tert-butoxycarbonyl)amino)propanoicacid (800 mg, 1.654 mmol, 59.6% yield) as greenish gum. (ESI) m/z: 484.1(M+H)⁺.

23B. Preparation of benzylN-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}ethyl]amino}phenyl)but-3-en-1-yl]carbamate

To a RBF was added(R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino)-3-((tert-butoxycarbonyl)amino)propanoicacid (800 mg, 1.654 mmol), THF (15 mL), Hunig's Base (0.867 mL, 4.96mmol), but-3-en-1-amine (235 mg, 3.31 mmol) and HATU (1258 mg, 3.31mmol). The reaction was stirred at rt for 3 h. The reaction waspartitioned between EtOAc (50 ml) and water (30 ml). The organic layerwas separated, washed with water (30 mL) and brine (30 ml), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give benzylN-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}ethyl]amino}phenyl)but-3-en-1-yl]carbamate(440 mg, 0.820 mmol, 49.6% yield) as a white solid. (ESI) m/z: 537.3(M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=5.3 Hz, 1H), 7.71 (d,J=8.8 Hz, 1H), 7.42-7.24 (m, 5H), 7.03 (t, J=7.8 Hz, 1H), 6.87 (t, J=5.8Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 6.51 (s, 1H), 6.37 (d, J=7.7 Hz, 1H),5.82-5.64 (m, 2H), 5.60 (d, J=6.4 Hz, 1H), 5.13-4.86 (m, 6H), 4.55-4.34(m, 1H), 3.83-3.61 (m, 1H), 3.32-3.26 (m, 1H), 3.25-2.99 (m, 3H),2.44-2.25 (m, 2H), 2.19-2.01 (m, 2H), 1.43-1.32 (m, 9H).

23C. Preparation of benzylN-[(3R,8E,11S)-3-({[(tert-butoxy)carbonyl]amino}methyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),8,12,14-tetraen-11-yl]carbamate

To a RBF was added benzylN-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}ethyl]amino}phenyl)but-3-en-1-yl]carbamate(385 mg, 0.717 mmol), pTsOH.H₂O (136 mg, 0.717 mmol) and DCE (70 mL).The reaction was purged with Ar for 15 min and then Grubbs II (122 mg,0.143 mmol) was added and the reaction was stirred at 50° C. under Arfor 5 h. The reaction was cooled and saturated aqueous NaHCO₃ (20 ml)was added and the reaction was stirred at rt for 15 min. The reactionmixture was separated. The organic layer was washed with water (30 ml)and brine (30 ml), dried over MgSO₄, filtered and concentrated. Theresidue was purified using ISCO system (0-10% CH₂Cl₂/MeOH gradient) togive product. The residue was then tritiated with CH₂Cl₂ (10 ml)/MeOH(10 ml)/EtOAc (5 ml)/heptane (15 ml). The solid was collected byfiltration to give benzylN-[(3R,8E,11S)-3-({[(tert-butoxy)carbonyl]amino}methyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),8,12,14-tetraen-11-yl]carbamate(135 mg, 0.265 mmol, 37.0% yield) as a light colored solid. (ESI) m/z:509.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (br. s., 5H), 7.16 (t,J=7.8 Hz, 1H), 6.70 (br. s., 1H), 6.64 (br. s., 1H), 6.59 (d, J=7.5 Hz,1H), 6.15 (br. s., 1H), 5.56 (br. s., 1H), 5.44 (br. s., 1H), 5.23 (br.s., 1H), 5.12 (s, 2H), 5.05-4.92 (m, 2H), 4.59 (br. s., 1H), 3.83 (br.s., 1H), 3.72-3.64 (m, 3H), 2.90-2.79 (m, 1H), 2.75-2.64 (m, 2H),2.14-2.05 (m, 1H), 1.98 (q, J=11.3 Hz, 1H), 1.48 (s, 9H).

23D. Preparation of tert-butylN-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate

To a 2-neck RBF was added benzylN-[(3R,8E,11S)-3-({[(tert-butoxy)carbonyl]amino}methyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),8,12,14-tetraen-11-yl]carbamate(135 mg, 0.265 mmol), EtOH (10 mL) and Pd/C (56.5 mg, 0.053 mmol). Thereaction was stirred under an atmosphere of hydrogen (balloon) for 6 h.The reaction was carefully filtered through Celite and the filtrate wasconcentrated to give tert-butylN-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate(99 mg, 0.263 mmol, 99% yield) as a beige solid. (ESI) m/z: 377.2(M+H)⁺.

23E. Preparation of tert-butylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate

tert-ButylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate (75 mg, 0.112 mmol, 42.7% yield) wasprepared in a similar manner as the procedure described in Example 1, byreplacing tert-butyl(7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate with tert-butylN-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate.(ESI) m/z: 667.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 8.36(s, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.78-7.72 (m, 1H), 7.69-7.66 (m, 1H),7.13 (t, J=7.8 Hz, 1H), 6.75-6.65 (m, 2H), 6.44 (s, 1H), 6.27 (d, J=7.7Hz, 1H), 5.69 (dd, J=13.0, 2.9 Hz, 1H), 4.14 (t, J=6.5 Hz, 1H),3.61-3.37 (m, 4H), 3.00 (dt, J=13.8, 4.5 Hz, 1H), 2.25 (t, J=12.2 Hz,1H), 2.00-1.80 (m, 3H), 1.64-1.54 (m, 1H), 1.48 (s, 9H), 1.26-1.15 (m,2H).

23F. Preparation of(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride

To a RBF was added(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride (15 mg, 0.022 mmol). MeOH (0.2 mL) and 4 N HCl in dioxane(0.034 mL, 1.123 mmol). The reaction was stirred at rt for 30 min. Thereaction was concentrated to give(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one, tri-hydrochloride salt (15 mg, 0.022 mmol, 99% yield)as a white solid. (ESI) m/z: 567.2 (M+H)⁺.

Example 23. Preparation of methylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamatetrifluoromethyl acetate

To a RBF was added(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol), THF (0.3 mL), Et₃N(9.78 μl, 0.070 mmol) and methyl chloroformate (1.087 μl, 0.014 mmol).The reaction was stirred at rt for 10 min. The reaction was purifiedusing RP prep-HPLC to give methylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl)}carbamatetrifluoromethyl acetate (2 mg, 2.60 μmol, 18.50% yield) as a whitesolid. (ESI) m/z: 625.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H),8.35 (d, J=0.7 Hz, 1H), 7.91-7.87 (m, 1H), 7.79-7.73 (m, 1H), 7.69-7.65(m, 1H), 7.13 (t, J=7.7 Hz, 1H), 6.73-6.67 (m, 2H), 6.43 (s, 1H), 6.29(d, J=7.7 Hz, 1H), 5.69 (dd, J=12.9, 2.5 Hz, 1H), 4.17 (t, J=6.4 Hz,1H), 3.69 (s, 3H), 3.56-3.46 (m, 3H), 3.00 (d, J=13.4 Hz, 1H), 2.30-2.19(m, 1H), 1.99-1.77 (m, 3H), 1.64-1.54 (m, 1H), 1.38-1.35 (m, 1H),1.23-1.12 (m, 2H). Analytical HPLC (Method A) RT=10.784 min, purity=96%.Factor XIa Ki=27 nM, Plasma Kallikrein Ki=2715 nM.

Example 24. Preparation ofN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}pyridine-3-carboxamidetrifluoromethylacetate

To a RBF was added(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol), nicotinic acid(1.728 mg, 0.014 mmol), THF (0.5 mL), Et₃N (9.78 μl, 0.070 mmol) andHATU (5.34 mg, 0.014 mmol). The reaction was stirred at rt for 1 h. Thereaction was purified using RP prep-HPLC to giveN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}pyridine-3-carboxamide trifluoromethyl acetate(8 mg, 7.93 μmol, 56.5% yield) as an off-white solid. (ESI) m/z: 672.1(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.11 (br. s., 1H), 8.81 (d, J=4.2 Hz,1H), 8.64 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.39 (d, J=5.5 Hz, 1H), 8.35(s, 1H), 7.94-7.87 (m, 1H), 7.82-7.72 (m, 2H), 7.70-7.62 (m, 1H), 7.14(t, J=7.8 Hz, 1H), 6.79-6.69 (m, 2H), 6.42 (s, 1H), 6.32 (d, J=7.5 Hz,1H), 5.68 (d, J=10.8 Hz, 1H), 4.35 (t, J=6.4 Hz, 1H), 3.90-3.76 (m, 2H),3.54 (br. s., 1H), 3.01 (d, J=13.2 Hz, 1H), 2.25 (t, J=10.1 Hz, 1H),1.98-1.91 (m, 1H), 1.83 (br. s., 2H), 1.59 (d, J=4.4 Hz, 1H), 1.40-1.10(m, 4H). Analytical HPLC (Method A) RT=8.844 min, purity=98%. Factor XIaKi=62 nM, Plasma Kallikrein Ki=5203 nM.

Example 25. Preparation of(15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione

25A. Preparation of1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-2-carboxylicacid

To a sealed tube was added tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate prepared as inintermediate 2, (S)-benzyl (1-(3-bromophenyl)but-3-en-1-yl)carbamate(0.92 g, 2.55 mmol), 5-oxopiperazine-2-carboxylic acid (0.442 g, 3.06mmol) and K₂CO₃ (1.059 g, 7.66 mmol) and DMSO (5.11 ml). The reactionwas purged with Ar and then CuI (24 mg, 0.13 mmol) was added. Thereaction was sealed and stirred at 110° C. for 48 h. The reaction waspartitioned between water (40 ml) and EtOAc (50 ml). The aqueous layerwas separated and treated with 1 N HCl until the pH is less than 4. Thenthe aqueous layer was extracted with EtOAc (2×30 ml). The combinedorganic layer was washed with brine (30 ml), dried over MgSO₄, filteredand concentrated to give1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-2-carboxylicacid (300 mg, 0.708 mmol, 27.7% yield) as light green oil. (ESI) m/z:424.5 (M+H)⁺.

25B. Preparation of benzyl((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl)but-3-en-1-yl)carbamate

To a RBF was added1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-2-carboxylicacid (300 mg, 0.708 mmol), THF (15 mL), Hunig's Base (0.371 mL, 2.125mmol), but-3-en-1-amine (235 mg, 3.31 mmol) and HATU (539 mg, 1.417mmol). The reaction was stirred at rt for 3.5 h. The reaction waspartitioned between EtOAc (50 ml) and water (30 ml). The organic layerwas separated, washed with water (30 mL) and brine (30 ml), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-100% EtOAc/Hex gradient) to give benzyl((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl)but-3-en-1-yl)carbamate(30 mg, 0.063 mmol, 8.89% yield) as a white solid. (ESI) m/z: 477.2(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (br. s., 5H), 7.31-7.26 (m, 1H),6.86 (d, J=7.5 Hz, 1H), 6.72 (br. s., 1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H),6.60 (br. s., 1H), 6.24 (br. s., 1H), 5.78-5.58 (m, 2H), 5.37 (br. s.,1H), 5.22-4.88 (m, 7H), 4.78 (d, J=4.4 Hz, 1H), 4.21 (dd, J=4.0, 2.0 Hz,1H), 4.09-3.90 (m, 3H), 3.64 (d, J=9.5 Hz, 1H), 3.34 (d, J=5.9 Hz, 2H),2.53 (br. s., 2H), 2.21 (br. s., 2H).

25C. Preparation of benzylN-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),12,16,18-tetraen-15-yl]carbamate

To a RBF was added benzyl((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl)but-3-en-1-yl)carbamate(30 mg, 0.063 mmol) and DCE (7 mL). The reaction was purged with Ar for5 min and then Grubbs II (10.69 mg, 0.013 mmol) was added and thereaction was stirred at 50° C. under Ar for 2.5 h. The reaction wasconcentrated and purified using ISCO system (0-100% EtOAc/Hex gradient)to give benzyl N-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),12,16,18-tetraen-15-yl]carbamate (25 mg, 0.056 mmol, 89% yield) as alight colored solid. (ESI) m/z: 477.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.38-7.20 (m, 6H), 6.73 (br. s., 1H), 6.65-6.47 (m, 2H), 6.32 (br. s.,1H), 6.18 (br. s., 1H), 5.52 (br. s., 2H), 5.07-4.88 (m, 3H), 4.81 (br.s., 1H), 4.23 (br. s., 1H), 4.04 (br. s., 1H), 3.96-3.81 (m, 2H), 3.56(br. s., 2H), 2.77 (d, J=12.3 Hz, 1H), 2.67 (d, J=12.3 Hz, 1H), 2.51 (d,J=9.9 Hz, 1H), 2.21-1.96 (m, 2H).

25D. Preparation of(15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione

To a 3-neck RBF was added benzylN-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),12,16,18-tetraen-15-yl]carbamate (25 mg, 0.056 mmol), EtOH (3 mL) andPd/C (11.86 mg, 0.011 mmol). The reaction was stirred under anatmosphere of hydrogen (balloon) for 1 h. The reaction was carefullyfiltered and the filtrate was concentrated to give(15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione(10 mg, 0.032 mmol, 56.7% yield) as a beige solid. (ESI) m/z: 317.2(M+H)⁺.

Example 25. Preparation of(15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione

(15S)-15-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione trifluoromethylacetate (4 mg, 5.27 μmol,16.66% yield) was prepared in a similar manner as the proceduredescribed in Example 1, by replacing tert-butyl(7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate with(15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione.(ESI) m/z: 607.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.30 (m, 1H),8.24 (s, 1H), 7.86-7.83 (m, 1H), 7.75-7.71 (m, 1H), 7.65-7.61 (m, 1H),7.33 (t, J=7.8 Hz, 1H), 6.96-6.89 (m, 2H), 6.79 (d, J=7.7 Hz, 1H), 6.44(d, J=0.4 Hz, 1H), 5.82 (dd, J=12.4, 3.2 Hz, 1H), 4.42 (t, J=4.0 Hz,1H), 4.21-4.07 (m, 2H), 3.88-3.72 (m, 2H), 3.22-3.11 (m, 1H), 2.51 (dt,J=13.0, 6.5 Hz, 1H), 1.90-1.72 (m, 2H), 1.57 (dd, J=12.5, 6.2 Hz, 1H),1.50-1.42 (m, 2H), 1.41-1.32 (m, 2H), 1.18-0.92 (m, 1H). Analytical HPLC(Method A) RT=10.106 min, purity=95%. Factor XIa Ki=51 nM, PlasmaKallikrein Ki=6748 nM.

Example 26. Preparation of tert-butylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethylacetate

tert-ButylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate,trifluoromethyl acetate (45 mg, 0.053 mmol) was prepared in a similarmanner as the procedure described in Example 23E, by replacing(R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid with(R)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid. (ESI) m/z:681.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.35 (s, 1H),8.31-8.25 (m, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.78-7.73 (m, 1H), 7.70-7.66(m, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.78-6.70 (m, 2H), 6.43 (s, 1H), 6.31(d, J=7.7 Hz, 1H), 5.70 (dd, J=13.0, 2.9 Hz, 1H), 4.08 (t, J=7.2 Hz,1H), 3.61-3.46 (m, 1H), 3.29-3.19 (m, 2H), 2.98 (d, J=11.4 Hz, 1H), 2.27(t, J=12.7 Hz, 1H), 2.00-1.81 (m, 6H), 1.69-1.55 (m, 1H), 1.48 (s, 9H),1.25-1.14 (m, 1H). Analytical HPLC (Method X) RT=3.831 min, purity=95%.Factor XIa Ki=24 nM, Plasma Kallikrein Ki=430 nM.

Example 27. Preparation of(3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride

To a RBF was added tert-butylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethylacetate (45 mg, 0.066 mmol) and 4 N HCl in dioxane (0.825mL, 3.30 mmol). The reaction was stirred at rt for 15 min. The reactionwas concentrated to give (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride (45 mg, 0.061 mmol, 93% yield) as off-white solid. (ESI)m/z: 581.4 (M+H)⁺. Analytical HPLC (Method X) RT=3.145 min, purity=95%.Factor XIa Ki=871 nM, Plasma Kallikrein Ki=14030 nM.

Example 28. Preparation of methylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethyl acetate

MethylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}) carbamate, trifluoromethyl acetate (8.5 mg,10.72 μmol, 74.0% yield) was prepared in a similar manner as theprocedure described in Example 23, by replacing(3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride with (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-onehydrochloride prepared as described in Example 27. (ESI) m/z: 639.2(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.35 (s, 1H), 7.89 (d,J=2.4 Hz, 1H), 7.77-7.73 (m, 1H), 7.69-7.65 (m, 1H), 7.20 (t, J=7.8 Hz,1H), 6.88-6.80 (m, 2H), 6.49 (d, J=7.5 Hz, 1H), 6.43-6.37 (m, 1H), 5.69(dd, J=12.8, 2.9 Hz, 1H), 4.11 (t, J=7.2 Hz, 1H), 3.68 (s, 3H),3.59-3.47 (m, 1H), 3.32-3.23 (m, 2H), 2.99-2.87 (m, 1H), 2.31 (td,J=12.4, 4.1 Hz, 1H), 2.04-1.92 (m, 3H), 1.84-1.70 (m, 2H), 1.68-1.59 (m,1H), 1.41-1.32 (m, 1H), 1.27-1.13 (m, 2H). Analytical HPLC (Method A)RT=10.956 min, purity=95%. Factor XIa Ki=5 nM, Plasma Kallikrein Ki=83nM.

Example 29. Preparation ofN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}-1-(difluoromethyl)-1H-pyrazole-3-carboxamidetrifluoromethyl acetate

To a RBF was added(3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol),1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (2.229 mg, 0.014 mmol),THF (0.5 mL), Et₃N (9.58 μl, 0.069 mmol) and HATU (5.23 mg, 0.014 mmol).The reaction was stirred at rt for 1 h. The reaction was purified usingRP prep-HPLC to giveN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}-1-(difluoromethyl)-1H-pyrazole-3-carboxamidetrifluoromethyl acetate (6 mg, 6.79 μmol, 49.4% yield) as an off-whitesolid. (ESI) m/z: 725.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H),8.34 (s, 1H), 8.18-8.14 (m, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.78-7.73 (m,1H), 7.69-7.65 (m, 1H), 7.60-7.58 (m, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.95(d, J=2.6 Hz, 1H), 6.80-6.74 (m, 2H), 6.42 (s, 1H), 6.35 (d, J=7.7 Hz,1H), 5.69 (dd, J=13.0, 2.6 Hz, 1H), 4.15 (t, J=7.0 Hz, 1H), 3.68-3.49(m, 3H), 2.99-2.91 (m, 1H), 2.34-2.22 (m, 1H), 2.17-2.02 (m, 2H),1.97-1.78 (m, 3H), 1.64-1.53 (m, 1H), 1.39-1.30 (m, 1H), 1.27-1.11 (m,2H). Analytical HPLC (Method X) RT=3.515 min, purity=95%. Factor XIaKi=5 nM, Plasma Kallikrein Ki=49 nM.

Example 30. Preparation of methylN-{2-[(3S,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethyl acetate

MethylN-{2-[(3S,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate,trifluoromethyl acetate (6.5 mg, 8.11 μmol) was prepared in a similarmanner as the procedure described in Example 28, by replacing(R)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid with(S)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid. (ESI) m/z:639.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.36-8.32 (m, 2H), 8.19 (dd,J=7.8, 2.8 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.75-7.71 (m, 1H), 7.66-7.61(m, 1H), 7.24-7.15 (m, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.84 (br. s., 1H),6.78-6.71 (m, 1H), 6.41 (d, J=0.7 Hz, 1H), 5.73 (dd, J=12.4, 3.2 Hz,1H), 3.96 (t, J=6.9 Hz, 1H), 3.70-3.64 (m, 3H), 3.40-3.27 (m, 3H),3.23-3.09 (m, 1H), 2.44 (dt, J=12.9, 6.4 Hz, 1H), 2.02 (ddt, J=17.6,13.8, 6.9 Hz, 2H), 1.95-1.83 (m, 1H), 1.80-1.64 (m, 1H), 1.62-1.50 (m,1H), 1.45 (quin, J=6.6 Hz, 2H), 1.31-1.12 (m, 2H). Analytical HPLC(Method A) RT=9.937 min, purity=94%. Factor XIa Ki=515 nM, PlasmaKallikrein Ki=5682 nM.

Example 31. Preparation of methylN-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate,trifluoromethylacetate

31A. Preparation of tert-butylN-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate

tert-ButylN-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl)}carbamate(95 mg, 0.182 mmol) was prepared in a similar manner as the proceduredescribed in Example 23D, by replacing(R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid with(S)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid. (ESI) m/z:391.2 (M+H)⁺.

31B. Preparation of tert-butylN-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethyl acetate

To a RBF was added tert-butylN-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate (13 mg, 0.033 mmol), intermediate 13(9.16 mg, 0.033 mmol), HATU (18.99 mg, 0.050 mmol), Hunig's Base (0.012mL, 0.067 mmol) and DMF (0.5 mL). The reaction was stirred at rt for 16h. The reaction was diluted with MeOH and a few drops of water andpurified using RP prep-HPLC system. The desired peak was concentrated togive tert-butylN-{2-[(3S,11S)-1-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl)}carbamate, trifluoromethyl acetate (17 mg, 0.022mmol, 67.1% yield) as an off-white solid. (ESI) m/z: 669.4 (M+Na)⁺.

31C. Preparation ofN-[(3S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-11-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide,hydrochloride

To a RBF was added tert-butylN-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl)}carbamate trifluoromethyl acetate (17 mg, 0.026mmol), dioxane (0.5 mL) and HCl (0.656 mL, 2.63 mmol). The reaction wasstirred at rt for 15 min. The reaction was concentrated to giveN-[(3S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-1-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide,trihydrochloride (17 mg, 0.026 mmol, 99% yield) as an off-white solid.(ESI) m/z: 547.1 (M+H)⁺.

Example 31. Preparation of methylN-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamatetrifluoromethylacetate

To a RBF was added N-[(3 S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-1-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide,hydrochloride (17 mg, 0.026 mmol), THF (0.5 mL), Et₃N (0.018 mL, 0.129mmol) and followed by methyl chloroformate (2.005 μl, 0.026 mmol). Thereaction was stirred at rt for 10 min. The reaction was purified usingRP prep-HPLC to give methylN-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethyl acetate (7 mg, 9.24μmol, 35.7% yield) as a white solid. (ESI) m/z: 605.4 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.24 (s, 1H), 7.94 (d, J=3.5 Hz, 1H), 7.77 (ddd,J=8.2, 6.8, 1.5 Hz, 1H), 7.52 (ddd, J=8.0, 6.5, 1.8 Hz, 1H), 7.46-7.35(m, 2H), 7.23-7.10 (m, 2H), 6.98 (br. s., 1H), 4.90 (d, J=4.6 Hz, 1H),3.94 (t, J=7.0 Hz, 1H), 3.67 (s, 3H), 3.41-3.26 (m, 3H), 3.09 (d, J=10.3Hz, 1H), 2.20-2.02 (m, 3H), 1.99-1.83 (m, 1H), 1.54 (br. s., 1H), 1.41(d, J=4.6 Hz, 1H), 1.38-1.31 (m, 2H), 0.83-0.69 (m, 1H), 0.59 (d, J=6.6Hz, 1H). Analytical HPLC (Method A) RT=6.516 min, purity=95%. Factor XIaKi=1834 nM, Plasma Kallikrein Ki=9494 nM.

Example 32. Preparation of(6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),14,16-triene-3,7-dione

32A. Preparation of(R)—N-[(1E)-(3-Bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in DCM (200ml) was added (R)-2-methylpropane-2-sulfinamide (14.96 g, 123 mol) andCs₂CO₃ (40.2 g, 123 mol). The reaction mixture was stirred at rtovernight. After this time, the reaction mixture was filtered andconcentrated to give a yellow oil. The yellow oil was purified using a120 g silica gel ISCO column eluted with hexanes and EtOAc to give(R)—N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide(35 g, 93%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d6) δ 8.58-8.55 (m,1H), 8.05-7.98 (m, 1H), 7.84-7.76 (m, 2H), 1.20 (s, 9H). LCMS m/z 306.1(M+H).

32B. Preparation of(R)—N-[(1S)-1-(3-Bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

N-[(1E)-(3-Bromo-5-fluorophenyl)methylidene]-2,2-dimethylpropanamide (35g, 114 mol) was dissolved in THF (500 ml) in a large 3 neck RBF andflushed with Ar. The solution was cooled to 0° C. and In powder (18.4 g,160 mol) was added followed by the dropwise addition of allylbromide(15.2 g, 126 mol). The reaction was stirred at 0° C. for 2 h, then theice bath was removed and the reaction mixture was stirred at rtovernight. The reaction was quenched with water (2 L) and the gelatinousmaterial was filtered through Celite®. The filtrate was concentrated invacuo to an oily mass. The crude material was dissolved in water (2 L)and the organics were extracted with EtOAc (4×200 ml), dried over MgSO₄,filtered and concentrated to give an oil. The oily liquid was purifiedvia a silica gel ISCO column and eluted with DCM/MeOH to afford(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(34.9 g, 88% yield) as a semi solid mass. LCMS m/z 348.2 (M+H). ¹H NMR(500 MHz, DMSO-d6) δ 7.44-7.38 (m, 2H), 7.26-7.20 (m, 1H), 5.79-5.65 (m,1H), 5.46-5.42 (m, 1H), 5.04-4.98 (m, 2H), 4.41-4.34 (m, 1H), 2.69-2.59(m, 1H), 2.49-2.43 (m, 1H), 1.09 (s, 9H)

32C. Preparation of tertbutyl-N-[(1S)-1-(3-Bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

To a cooled 0° C. solution of(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(21.9 g, 100 mol) dissolved in MeOH (100 ml) was added conc. HCl (50 ml)dropwise and then stirred at 0° C. for 48 h. After this time, thereaction mixture was concentrated to give a white solid mass. Theresidue was dissolved in water (1000 ml) and the organics were extractedwith EtOAc (2×200 ml), dried over MgSO₄, filtered and concentrated to abrown oil (11.5 g). The aqueous layer was basified with NaOH and theorganics were extracted with EtOAc (2×300 ml), dried over MgSO₄,filtered and concentrated to a brown oil (18 g). The combined oils weredissolved in DCM (500 ml) and to this was added Boc₂O (22 g) followed byTEA (15 ml) and the reaction mixture was stirred at rt overnight. Thereaction mixture was concentrated in vacuo and purified via a 330 gsilica gel Isco column eluting with hexanes and EtOAc to give a whitesolid. The white solid was triturated with hexanes and the precipitatewas collected by filtration to giveN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (29.5 g, 87%yield).

32D. Preparation of methyl(2R)-1-{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-5-fluorophenyl}-5-oxopyrrolidine-2-carboxylate

A mixture of (S)-tert-butyl(1-(3-bromo-5-fluorophenyl)but-3-en-1-yl)carbamate (0.5 g, 1.453 mmol),(R)-methyl 5-oxopyrrolidine-2-carboxylate (0.250 g, 1.743 mmol), CsF(0.552 g, 3.63 mmol), N,N′-dimethylethylene diamine (0.016 ml, 0.145mmol) in THF (2.91 ml) was degassed with Ar. CuI (0.014 g, 0.073 mmol)was added and the reaction was stirred for 72 h. The mixture was dilutedwith EtOAc and quenched with saturated aqueous NH₄Cl. The aqueous layerwas extracted with EtOAc (2×). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered and concentrated. The crude residuewas purified with silica gel chromatography eluting with 0-100% EtOAc inhexanes. The collected fractions were concentrated to give 366 mg (62%)of white solid. LCMS m/z 351.4 (M+H-tbutyl)⁺. ¹H NMR (400 MHz, CHCl₃-d)δ 7.36-7.29 (m, 1H), 7.12 (s, 1H), 6.79 (dt, J=9.0, 1.7 Hz, 1H), 5.64(ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.17-5.07 (m, 2H), 4.86 (br. s., 1H),4.76-4.65 (m, 2H), 3.77-3.73 (m, 3H), 2.76 (dt, J=16.7, 9.5 Hz, 1H),2.62-2.55 (m, 1H), 2.53-2.42 (m, 3H), 2.18 (ddt, J=12.6, 9.6, 2.8 Hz,1H), 1.48 (br. s., 9H).

32E. Preparation of(2R)-1-{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-5-fluoronhenyl}-5-oxopyrrolidine-2-carboxylicacid

To (R)-methyl 1-(3-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-fluorophenyl)-5-oxopyrrolidine-2-carboxylate(0.366 g, 0.900 mmol) in THF (5 ml)/water (2 ml), cooled to 0° C., wasadded LiOH.H₂O (0.151 g, 3.60 mmol). After 2 h, the reaction waspartitioned with 1 N HCl (5 ml) and EtOAc (30 ml). The aqueous layer wasextracted with EtOAc (2×20 ml). The combined organic layers were washedwith brine (15 ml) and dried (MgSO₄). Filtration and concentrationafforded 0.35 g (99%) white solid. LCMS m/z 337.4 (M+H-tbutyl)⁺. ¹H NMR(400 MHz, CHCl₃-d) δ 7.02-6.83 (m, 1H), 6.74 (br. s., 2H), 5.72-5.54 (m,1H), 5.06 (d, J=11.0 Hz, 2H), 4.77 (br. s., 1H), 2.91-2.72 (m, 1H),2.62-2.47 (m, 2H), 2.41 (br. s., 2H), 2.29 (br. s., 1H), 1.51-1.25 (m,9H)

32F. Preparation of tert-butylN-[(1S)-1-{3-fluoro-5-[(5R)-2-oxo-5-[(prop-2-en-1-yl)carbamoyl]pyrrolidin-1-yl]phenyl}but-3-en-1-yl]carbamate

To(R)-1-(3-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-fluorophenyl)-5-oxopyrrolidine-2-carboxylicacid (0.357 g, 0.910 mmol) in DCM (5 ml), cooled to 0° C., was addedprop-2-en-1-amine (0.052 g, 0.910 mmol), pyridine (0.368 ml, 4.55 mmol)and POCl₃ (0.085 ml, 0.910 mmol). After 30 min, the reaction wasquenched with saturated aqueous NaHCO₃ (5 ml) and extracted with EtOAc(3×10 ml). The combined organic layers were washed with brine (5 ml) anddried (MgSO₄). The crude residue was purified with silica gelchromatography eluting with 0-100% EtOAc in hexanes. The collectedfractions were concentrated to give 248 mg (63%) of white solid. LCMSm/z 376.4 (M+H-tbutyl).⁺

32G. Preparation of tert-butylN-[(6R,10E,13S)-16-fluoro-3,7-dioxo-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),10,14,16-tetraen-13-yl]carbamate

To tert-butylN-[(1S)-1-{3-fluoro-5-[(5R)-2-oxo-5-[(prop-2-en-1-yl)carbamoyl]pyrrolidin-1-yl]phenyl}but-3-en-1-yl]carbamatein DCE (37 ml), degassed with Ar, was added Grubbs II (0.102 g, 0.121mmol) and reaction was heated to 40° C.

After 48 h, the reaction was concentrated and the residue was purifiedwith silica gel chromatography eluting with DCM/0-10% MeOH. The materialwas re-purified by reverse phase HPLC to afford 6 mgs (4.9%) of a whitesolid. LCMS m/z 348.3 (M+H-tbutyl).⁺ ¹H NMR (400 MHz, CH₃Cl-d) δ 7.83(br. s., 1H), 6.83 (d, J=8.6 Hz, 1H), 6.29 (br. s., 1H), 5.84 (br. s.,1H), 5.74 (dt, J=15.4, 7.6 Hz, 1H), 5.13 (br. s., 1H), 4.91 (br. s.,1H), 4.62 (br. s., 1H), 4.44 (br. s., 1H), 3.78 (br. s., 1H), 3.61 (br.s., 1H), 2.80-2.59 (m, 2H), 2.50 (d, J=7.0 Hz, 2H), 2.21-2.12 (m, 1H),2.05 (br. s., 1H), 1.56-1.20 (m, 9H).

32F. Preparation of(6R,13S)-13-amino-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),14,16-triene-3,7-dione

tert-ButylN-[(6R,10E,13S)-16-fluoro-3,7-dioxo-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),10,14,16-tetraen-13-yl]carbamate(6 mg, 0.015 mmol) in EtOH (5 ml) was placed under a hydrogen atmosphereat 55 psi in the presence of PtO₂ (3 mg). After 5 h, the reactionmixture was filtered and the filtrate was concentrated. The reducedproduct was deprotected in 50% TFA/DCM (2 ml). After 24 h, the reactionmixture was concentrated to dryness and the product was taken up inDCM/MeOH and filtered through a basic cartridge and the filtrateconcentrated to give (4 mg, 88%) of free base. LCMS m/z 306.08 (M+H).⁺

Example 32. Preparation of((6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),14,16-triene-3,7-dione

To6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol,6-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-olprepared in Intermediate 7, (4.27 mg, 0.013 mmol) and HATU (6.48 mg,0.017 mmol) in a small vial was added DBU (2.96 μl, 0.020 mmol) in AcN(0.2 ml). After 30 min.,(6R,13S)-13-amino-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)] octadeca-1(18),14,16-triene-3,7-dione (0.004 g, 0.013 mmol) was added with DMF(0.2 ml) and the reaction was stirred 24 h. The reaction mixture wasfiltered and purified by reverse phase HPLC to afford(6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),14,16-triene-3,7-dione(1.8 mgs, 21%). LCMS m/z 614.4 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d6) δ 8.73(d, J=7.3 Hz, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 8.01 (t, J=8.1 Hz, 1H),7.77-7.64 (m, 2H), 7.19-7.09 (m, 1H), 6.68 (s, 1H), 6.46 (d, J=9.2 Hz,1H), 5.57 (d, J=10.4 Hz, 1H), 4.87 (t, J=7.5 Hz, 1H), 2.72-2.60 (m, 3H),2.36-2.25 (m, 2H), 2.10 (br. s., 1H), 2.03-1.97 (m, 1H), 1.55-1.44 (m,2H), 1.20 (br. s., 1H), 1.05 (d, J=6.1 Hz, 2H). Analytical HPLC (MethodC) RT=1.475 min, purity=96%; Factor XIa Ki=77.5 nM, Plasma Kallikrein Ki5304 nM.

Example 33(6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione

33A. Preparation of(6R,14S)-14-amino-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione

(6R,14S)-14-amino-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1 (19),15,17-triene-3,7-dione was made in a similar manner as(6R,13S)-13-amino-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)] octadeca-1(18),14,16-triene-3,7-dione by substituting (S)-tert-butyl(1-(3-bromophenyl)but-3-en-1-yl)carbamate, tert-butylN-[(1S)-1-(3-bromophenyl)but-3-en-1-yl] carbamate prepared as describedin Intermediate 1, for (S)-tert-butyl(1-(3-bromo-5-fluorophenyl)but-3-en-1-yl)carbamate and but-3-en-1-aminefor prop-2-en-1-amine to afford (41 mg, 50%) as a dark solid. LCMS m/z302.08 (M+H).⁺

Example 33. Preparation of(6R,14S)-14-(4-{5-chloro-2-[14-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione

To6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-olprepared as described in Intermediate 6 (0.018 g, 0.053 mmol) and HATU(0.026 g, 0.069 mmol) in a small vial was added DBU (0.012 ml, 0.080mmol) in AcN (0.4 ml). After 30 min,(6R,14S)-14-amino-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione (0.016 g, 0.053 mmol) was added in DMF (0.2 ml).After 24 h, the reaction mixture was purified by reverse phase HPLC andfreeze-dried to afford (7.8 mg, 22%) of a white solid. LCMS(ESI) m/z:626.08 (M+H).⁺ ¹H NMR (400 MHz, CD₃OD-d4) δ 7.97-7.89 (m, 2H), 7.82-7.76(m, 1H), 7.75-7.69 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.21-7.15 (m, 1H),6.99-6.87 (m, 1H), 6.52-6.44 (m, 1H), 5.74 (dd, J=13.2, 3.1 Hz, 1H),5.02-4.94 (m, 1H), 3.68-3.54 (m, 1H), 2.93-2.84 (m, 1H), 2.77-2.68 (m,2H), 2.55-2.42 (m, 2H), 2.38-2.33 (m, 2H), 2.21-2.11 (m, 1H), 2.03-1.92(m, 2H), 1.89-1.79 (m, 2H), 1.72-1.64 (m, 1H), 1.45-1.32 (m, 2H),1.14-1.05 (m, 1H). Analytical HPLC (Method A) RT=8.18 min, purity=95%;Factor XIa Ki=12 nM, Plasma Kallikrein Ki 319.2 nM.

Example 34. Preparation of(6R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione

(6R,14S)-14-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione (10.9 mg, 28%) was prepared in asimilar manner as(6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione substituting6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-olfor6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol.LCMS(ESI) m/z: 610.3 (M+H). 1H NMR (500 MHz, CD₃OD) δ 8.68 (s, 1H),8.43-8.29 (m, 1H), 7.95 (dd, J=8.1, 1.5 Hz, 1H), 7.87 (dd, J=8.7, 7.6Hz, 1H), 7.63-7.55 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.87(d, J=7.7 Hz, 1H), 6.62 (s, 1H), 5.75 (dd, J=13.1, 2.9 Hz, 1H), 4.95 (t,J=7.4 Hz, 1H), 3.80 (s, 1H), 3.69-3.57 (m, 1H), 2.89 (dt, J=13.8, 4.2Hz, 1H), 2.77-2.64 (m, 2H), 2.52-2.41 (m, 1H), 2.41-2.34 (m, 1H),2.23-2.09 (m, 1H), 2.00-1.93 (m, 1H), 1.86-1.75 (m, 2H), 1.71-1.61 (m,1H), 1.49-1.28 (m, 2H), 1.08 (d, J=12.7 Hz, 1H). Analytical HPLC (MethodC) RT=1.53 min, purity=100%; Factor XIa Ki=6 nM, Plasma Kallikrein Ki133.5 nM.

Example 35. Preparation of(6S,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione

(6S,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1l-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione(14 mg, 27.9%) was prepared in a similar manner as(6R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione substituting (S)-ethyl5-oxopyrrolidine-2-carboxylate for (R)-ethyl5-oxopyrrolidine-2-carboxylate. LCMS(ESI) m/z: 610.08 (M+H).⁺ ¹H NMR(400 MHz, CD₃OD) δ 8.42-8.34 (m, 1H), 8.34-8.28 (m, 2H), 8.09 (dd,J=8.3, 1.2 Hz, 1H), 7.93-7.82 (m, 1H), 7.60-7.53 (m, 1H), 7.44 (t, J=8.0Hz, 1H), 7.22 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.69-6.60 (m, 1H), 5.81(dd, J=12.4, 3.4 Hz, 1H), 3.69-3.55 (m, 1H), 3.52-3.45 (m, 1H),3.10-2.97 (m, 1H), 2.86-2.71 (m, 1H), 2.71-2.59 (m, 1H), 2.53-2.43 (m,2H), 2.21-2.11 (m, 1H), 2.01-1.92 (m, 1H), 1.75-1.61 (m, 2H), 1.41-1.33(m, 3H). Analytical HPLC (Method A) RT=7.54 min, purity=97%; Factor XIaKi=5168 nM, Plasma Kallikrein Ki 11,140 nM.

Example 36. Preparation of(6R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-trien-7-one

(6R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-trien-7-one(5.1 mg, 8%) was prepared in a similar manner as(6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1l-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione substituting K₂CO₃ for CsF,(R)-pyrrolidine-2-carboxylic acid for (R)-methyl5-oxopyrrolidine-2-carboxylate and6-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] pyrimidin-4-olprepared in intermediate 5 for6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol.LCMS(ESI) m/z: 578.3 (M+H).⁺ ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H),8.36 (s, 1H), 8.24 (d, J=4.8 Hz, 1H), 7.93-7.89 (m, 1H), 7.80-7.75 (m,1H), 7.72-7.67 (m, 1H), 7.21 (t, J=7.9 Hz, 1H), 6.69-6.60 (m, 2H), 6.45(d, J=0.9 Hz, 1H), 6.18 (d, J=7.9 Hz, 1H), 5.73 (dd, J=12.5, 2.6 Hz,1H), 4.37 (dd, J=8.4, 4.8 Hz, 1H), 3.66-3.52 (m, 2H), 3.50-3.42 (m, 1H),3.13-3.02 (m, 1H), 2.47-2.37 (m, 1H), 2.28-2.16 (m, 2H), 2.11-2.03 (m,2H), 1.96-1.84 (m, 2H), 1.61 (dd, J=9.8, 5.6 Hz, 1H), 1.41-1.25 (m, 3H).Analytical HPLC (Method A) RT=8.89 min, purity=95%; Factor XIa Ki=8 nM,Plasma Kallikrein Ki 133.2 nM.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: L is independently selected from

is an optional bond; Q is independently selected from O, NH, and CH₂; Yis independently selected from N and CR⁷; ring A is independentlyselected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkylsubstituted with 0-4 R^(e), OR^(b), and C₃₋₅ cycloalkyl substituted with1-4 R⁶; R³ is independently selected from H, C₁₋₄ alkyl substituted with1-5 R⁵, C₂₋₄ alkenyl substituted with 1-5 R⁵, C₂₋₄ alkynyl substitutedwith 1-5 R⁵, CN, —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R^(c),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; R^(3a) is independently selected from H and C₁₋₄alkyl;alternatively, R^(3a) and R³ are taken together to form a heterocyclicring selected from

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; R^(3c) is independently selected from H, NO₂, ═O, halogen, C₁₋₄alkyl substituted with 1-5 R⁵, C₂₋₄ alkenyl substituted with 1-5 R⁵,C₂₋₄ alkynyl substituted with 1-5 R⁵, CN, —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R, —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R^(c),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; R⁴ is independently selected from H, halogen, CN,—(CH₂)_(n)NR^(a)R^(a), C₁₋₆ alkyl substituted with 1-5 R¹⁰,—(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R_(b), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—(CH₂)_(n)—NR^(a)C(N—CN)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(NH)NR^(a)R^(a),—(CH₂)_(n)—N═CR^(b)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═O)NR^(a)R^(a),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)C(═S)NR^(a)C(═O)R^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CH₂)_(n)—NR^(a)S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—NR^(a)S(═O)_(p)R_(c),—(CH₂)_(n)-aryl substituted with 1-5 R¹⁰, —(CH₂)_(n)—C₃₋₆ cycloalkylsubstituted with 1-5 R¹⁰, and —(CH₂)_(n)-4-6 membered heterocyclylsubstituted with 1-5 R¹⁰; R⁵, at each occurrence, is independentlyselected from H, D, —(CH₂)_(n)—OR^(b), ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—C₃₋₁₀ carbocyclyl substituted with 0-5 R^(e), —(CH₂)_(n)-4-to 10-membered heterocyclyl substituted with 0-5 R^(e), and —O-4- to10-membered heterocyclyl substituted with 0-5 R^(e); R⁶ is independentlyselected from H, OH, ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄ alkyl, —(CH₂)_(n)—OC₁₋₄alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle substituted with 0-5 R^(e),—(CH₂)_(n)-4- to 10-membered heterocycle substituted with 0-5 R^(e), and—(CH₂)_(n)-4- to 10-membered heterocycle substituted with 0-5 R^(e); R⁷is independently selected from H, CN, OR^(b), halogen, NR^(a)R^(a), andC₁₋₃ alkyl substituted with 0-5 R^(e); R⁸ is independently selected fromH, OH, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, CN, C₃₋₆ cycloalkyl,aryl, and 5- to 6-membered heterocycle; R¹⁰, at each occurrence, isindependently selected from H, halogen, CN, NO₂, ═O, C(═O)NR^(a)R^(a),C(═O)OR^(b), —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e), aryl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-5 R^(e),—(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with 0-5 R^(e);R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e); R^(b), at each occurrence, is independently selected from H, C₁₋₆alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynylsubstituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl; R^(d), ateach occurrence, is independently selected from H and C₁₋₄alkylsubstituted with 0-5 R^(e); R^(e), at each occurrence, is independentlyselected from F, Cl, Br, CN, NO₂, ═O, C₁₋₆ alkyl substituted with 0-5R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heterocyclyl, CO₂H, —(CH₂)_(n)OR^(f),SR^(f), and —(CH₂)_(n)NR^(f)R^(f); R^(f), at each occurrence, isindependently selected from H, C₁₋₅ alkyl optionally substituted with F,Cl, Br, C₃₋₆ cycloalkyl, and phenyl, or R^(f) and R^(f) together withthe nitrogen atom to which they are both attached form a heterocyclicring optionally substituted with C₁₋₄alkyl; n, at each occurrence, is aninteger independently selected from 0, 1, 2, 3, and 4; and p, at eachoccurrence, is an integer independently selected from 0, 1, and
 2. 2.The compound of claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: L is independentlyselected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkyl,OR^(b), and C₃₋₅ cycloalkyl; R³ is independently selected from H, C₁₋₄alkyl substituted with 1-5 R⁵, C₂₋₄ alkenyl substituted with 1-5 R⁵,C₂₋₄ alkynyl substituted with 1-5 R⁵, CN, —OR^(b),—(CH₂)_(n)—NR^(a)R^(a), —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a),—NR^(a)C(═S)NR^(a)C(═O)R^(b), —S(═O)_(p)R_(c), —S(═O)_(p)NR^(a)R^(a),—NR^(a)S(═O)_(p)NR^(a)R^(a), —NR^(a)S(═O)_(p)R^(c), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 1-5 R⁵, and —(CH₂)_(n)-4- to 10-memberedheterocyclyl substituted with 1-5 R⁵; R^(3a) is independently selectedfrom H and C₁₋₄alkyl; alternatively, R^(3a) and R³ are taken together toform a heterocyclic ring selected from

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; R^(3c) is independently selected from H, NO₂, ═O, halogen, and C₁₋₄alkyl substituted with 1-5 R⁵; R⁴ is independently selected from H,halogen, CN, C₁₋₆ alkyl substituted with 1-5 R¹⁰, —OR^(b),—(CH₂)_(n)-aryl substituted with 1-5 R¹⁰, —(CH₂)_(n)—C₃₋₆ cycloalkylsubstituted with 1-5 R¹⁰, and —(CH₂)_(n)-4-6 membered heterocyclylsubstituted with 1-5 R¹⁰; R⁵, at each occurrence, is independentlyselected from H, D, —(CH₂)_(n)—OR^(b), ═O, —(CH₂)_(n)NH₂, —(CH₂)_(n)CN,halogen, C₁₋₆ alkyl, —(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—C₃₋₁₀ carbocyclyl substituted with 0-5 R^(e), —(CH₂)_(n)-4-to 10-membered heterocyclyl substituted with 0-5 R^(e), and —O-4- to10-membered heterocyclyl substituted with 0-5 R^(e); R⁷ is independentlyselected from H, OR^(b), halogen, NR^(a)R^(a), and C₁₋₃ alkyl; R¹⁰, ateach occurrence, is independently selected from H, halogen, CN, NO₂, ═O,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆ alkyl substituted with 0-5R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substitutedwith 0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl substituted with 0-5 R^(e); R^(a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b), at each occurrence,is independently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynylsubstituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl; R^(e), ateach occurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O,C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heterocyclyl,CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and —(CH₂)_(n)NR^(f)R^(f); R^(f), ateach occurrence, is independently selected from H, C₁₋₅ alkyl optionallysubstituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl, or R^(f) andR^(f) together with the nitrogen atom to which they are both attachedform a heterocyclic ring optionally substituted with C₁₋₄alkyl; n, ateach occurrence, is an integer independently selected from 0, 1, 2, 3,and 4; and p, at each occurrence, is an integer independently selectedfrom 0, 1, and
 2. 3. The compound of claim 2 having Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: L is independently selected from

ring A is independently selected from

R¹ and R² are independently selected from H, halogen, C₁₋₄ alkyl, andOH; R³ is independently selected from —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a); R^(3a) is independentlyselected from H and C₁₋₄alkyl; alternatively, R^(3a) and R³ are takentogether to form a heterocyclic ring selected from

R^(3b) is independently selected from H, C₁₋₄ alkyl substituted with 1-5R⁵, —(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—NHC(═O)OR^(b),—(CH₂)_(n)—S(═O)_(p)R^(c), —(CH₂)_(n)—S(═O)_(p)NR^(a)R^(a),—(CR^(d)R^(d))_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5 R⁵, and—(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substituted with 1-5R⁵; R^(3c) is independently selected from H, ═O, and C₁₋₄ alkylsubstituted with 1-5 R⁵; R^(4a) is independently selected from H,halogen, CN, OCH₃, OCF₃, CH₃, C(═O)CH₃, CHF₂, CF₃, CCH₃F₂, OCHF₂, aryl,C₃₋₆ cycloalkyl, and 4-6 membered heterocycle, wherein said aryl,cycloalkyl and heterocycle is optionally substituted with R¹⁰; R^(4b) isindependently selected from H and halogen; R^(4c) is independentlyselected from H, F, Cl, methyl, ethyl, isopropyl, and OCH₃; R⁵, at eachoccurrence, is independently selected from H, D, —(CH₂)_(n)—OR^(b), ═O,—(CH₂)_(n)NH₂, —(CH₂)_(n)CN, halogen, C₁₋₆ alkyl,—(CH₂)_(n)—C(═O)OR^(b), —(CH₂)_(n)—OR^(b), —(CH₂)_(n)—C₃-10 carbocyclylsubstituted with 0-5 R^(e), —(CH₂)_(n)-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e), and —O-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e); R⁷ is independently selected from H and C₁₋₃alkyl; R¹⁰, at each occurrence, is independently selected from H,halogen, CN, NO₂, ═O, C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C(═NOH)NH₂, C₁₋₆ alkyl substituted with 0-5R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substitutedwith 0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-memberedheterocyclyl substituted with 0-5 R^(e); R^(a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b), at each occurrence,is independently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynylsubstituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl; R^(e), ateach occurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O,C₁₋₆ alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heterocyclyl,CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and —(CH₂)_(n)NR^(f)R^(f); R^(f), ateach occurrence, is independently selected from H, C₁₋₅ alkyl optionallysubstituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl, or R^(f) andR^(f) together with the nitrogen atom to which they are both attachedform a heterocyclic ring optionally substituted with C₁₋₄alkyl; n, ateach occurrence, is an integer independently selected from 0, 1, 2, 3,and 4; and p, at each occurrence, is an integer independently selectedfrom 0, 1, and
 2. 4. The compound of claim 3 having Formula (III):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R^(3b) is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),(CH₂)_(n)—C(═O)NR^(a)R^(a), —(CH₂)_(n)—S(═O)_(p)R^(c),—S(═O)_(p)NR^(a)R^(a), —(CH₂)_(n)—C₃₋₁₀ carbocyclyl substituted with 1-5R⁵, and —(CR^(d)R^(d))_(n)-4- to 10-membered heterocyclyl substitutedwith 1-5 R⁵; R^(3c) is independently selected from H and ═O; R^(4a) isindependently selected from H, F, Cl, Br, CN, OCH₃, OCF₃, CH₃,C(═O)C₁₋₄alkyl, C(═O)OC₁₋₄alkyl, CHF₂, CF₃, CCH₃F₂, OCHF₂,

R^(4b) is independently selected from H and F; R^(4c) is independentlyselected from H, F, Cl, methyl, ethyl, isopropyl, and OCH₃; R¹⁰, at eachoccurrence, is independently selected from H, F, Cl, Br,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with 0-5 R^(e), arylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with0-5 R^(e); R^(a), at each occurrence, is independently selected from H,C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 Re, —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c), at eachoccurrence, is C₁-6 alkyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, C₁₋₆alkyl substituted with 0-5 R^(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heterocyclyl,CO₂H, —(CH₂)_(n)OR^(f), SR^(f), and —(CH₂)_(n)NR^(f)R^(f); R^(f), ateach occurrence, is independently selected from H, C₁₋₅ alkyl optionallysubstituted with F, Cl, Br, C₃₋₆ cycloalkyl, and phenyl; n, at eachoccurrence, is an integer independently selected from 0, 1, 2, 3, and 4;and p, at each occurrence, is an integer independently selected from 0,1, and
 2. 5. The compound of claim 4, or a stereoisomer, a tautomer, ora pharmaceutically acceptable salt thereof, wherein: R^(3b) isindependently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, —C(═O)NR^(a)R^(a), and-4- to 5-membered heterocyclyl substituted with 1-5 R⁵; R^(3c) isindependently selected from H and ═O;

is independently selected from

R⁵, at each occurrence, is independently selected from H,—C(═O)OC₁₋₄alkyl, OC₁₋₄alkyl; R¹⁰, at each occurrence, is independentlyselected from H, F, Cl, Br, C(═O)NR^(a)R^(a), C(═O)OR^(b),—(CH₂)_(n)—OR^(b), —(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with0-5 R^(e), aryl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkylsubstituted with 0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclylsubstituted with 0-5 R^(e); and n, at each occurrence, is an integerindependently selected from 0, 1, 2, and
 3. 6. The compound of claim 3having Formula (IV):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R^(3b) is independently selected from H, C₁₋₄ alkyl,—C(═O)C₁₋₄alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl,—C(═O)NR^(a)R^(a), and -4- to 5-membered heterocyclyl substituted with1-5 R⁵; R^(3c) is independently selected from H and ═O;

is independently selected from

R¹⁰, at each occurrence, is independently selected from H, F, Cl, Br,C(═O)NR^(a)R^(a), C(═O)OR^(b), —(CH₂)_(n)—OR^(b),—(CH₂)_(n)—NR^(a)R^(a), C₁₋₆ alkyl substituted with 0-5 R^(e), arylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with0-5 R^(e), —(CH₂)_(n)—O-4- to 10-membered heterocyclyl substituted with0-5 R^(e); and n, at each occurrence, is an integer independentlyselected from 0, 1, 2, and
 3. 7. The compound of claim 3 having Formula(V):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R^(3b) is independently selected from H, C₁₋₄ alkyl,—C(═O)C₁₋₄alkyl, —(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, and -4-to 5-membered heterocyclyl substituted with 1-5 R⁵; R^(3c) isindependently selected from H and ═O; R^(4b) is independently selectedfrom H and F; R^(4c) is independently selected from H, F, Cl, methyl,ethyl, isopropyl, and OCH₃; R⁷ is independently selected from H and C₁₋₃alkyl; and n, at each occurrence, is an integer independently selectedfrom 0, 1, 2, and
 3. 8. The compound of claim 3, or a stereoisomer, atautomer, or a pharmaceutically acceptable salt thereof, wherein: L isindependently selected from

ring A is

R¹ and R² are independently selected from H, C₁₋₄ alkyl, and OH; R³ isindependently selected from —(CH₂)_(n)—NR^(a)R^(a),—(CH₂)_(n)—C(═O)R^(b), —(CH₂)_(n)—C(═O)OR^(b),—(CH₂)_(n)—NR^(a)C(═O)OR^(b), —(CH₂)_(n)—NR^(a)C(═O)R^(b),—NR^(a)C(═O)NR^(a)R^(a), —C(═O)NR^(a)R^(a); R^(3a) is H; alternatively,R^(3a) and R³ are taken together to form a heterocyclic ring selectedfrom

R^(3b) is independently selected from H, C₁₋₄ alkyl, —C(═O)C₁₋₄alkyl,—(CH₂)_(n)—C(═O)OH, —(CH₂)_(n)—C(═O)OC₁₋₄alkyl, —C(═O)NR^(a)R^(a), and-4- to 6-membered heterocyclyl substituted with 1-5 R⁵; R^(3c) isindependently selected from H and ═O;

is independently selected from

R⁵, at each occurrence, is independently selected from H,—C(═O)OC₁₋₄alkyl, OC₁₋₄alkyl; R⁷ is independently selected from H andC₁₋₃ alkyl; R^(a), at each occurrence, is independently selected from H,C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂,═O, C₁₋₆alkyl, haloalkyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heterocyclyl, and CO₂H; and n, at each occurrence, is aninteger independently selected from 0, 1, 2, and
 3. 9. A pharmaceuticalcomposition comprising one or more compounds according to claim 1 and apharmaceutically acceptable carrier or diluent.
 10. A method for thetreatment of a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1, or a stereoisomer, a tautomer, or a pharmaceuticallyacceptable salt thereof, wherein the thromboembolic disorder is selectedfrom arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, and thromboembolic disorders inthe chambers of the heart or in the peripheral circulation.
 11. A methodaccording to claim 10, wherein the thromboembolic disorder is selectedfrom unstable angina, an acute coronary syndrome, atrial fibrillation,myocardial infarction, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis.
 12. A compoundselected from tert-butyl (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one;methyl (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;tert-butyl (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;(7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-3,8-dione;tert-butyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one;methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;tert-butyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetate;(7R,15S)-5-acetyl-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one;(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-methyl-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one;2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]acetic acid; tert-butyl(7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0^(2,7)]nonadeca-1(19),15,17-triene-5-carboxylate; (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-(oxetan-3-yl)-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-8-one; ethyl2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-5-yl]-1,3-oxazole-5-carboxylate; tert-butyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;tert-butyl(7R,15S)-15-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-(20),16,18-triene-5-carboxylate;1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide; methyl(7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate;methyl(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-5-carboxylate; methylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12, 14-trien-3-yl]methyl)}carbamate; methylN-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl)}carbamate;N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}pyridine-3-carboxamide;(15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0^(2,7)]icosa-1(20),16,18-triene-4,8-dione; tert-butylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate;(3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one; methylN-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate;N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1l-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}-1-(difluoromethyl)-1H-pyrazole-3-carboxamide;methyl N-{2-[(3 S, 11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate;methyl N-{2-[(3 S, 11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate; (6R,13S)-13-{4[3-chloro-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),14,16-triene-3,7-dione;(6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione;(6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione;(6R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione;(6S,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-triene-3,7-dione;and(6R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0^(2,6)]nonadeca-1(19),15,17-trien-7-one;or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof.